First term

A member of the Nacionalista Party, Kalaw first entered politics in 1953 when she campaigned for Nacionalista presidential candidate and former Defense Secretary Ramon Magsaysay, who ran against the incumbent president Elpidio Quirino. In 1957, she also campaigned for Senator Claro M. Recto when he ran for president against incumbent president Carlos P. Garcia.^[8] During the Garcia administration, Kalaw headed the National Economic Protectionism Association, a non-government organization that staunchly promoted economic protectionism and promotion of Filipino businesses and products.^[8][12]

During the 1965 Senatorial Elections, Kalaw was part of the senatorial slate of the Nacionalista Party candidate Ferdinand Marcos and won.^[13] As senator, she introduced a total of 41 bills, including ones for salary increases of public school teachers (RA 5158); the creation of Local School Boards (RA 5447) and of the Barrio High School Charter/Magna Carta for Private Schools (RA 6054); the Educational Financing Act (RA 6728) and the inclusion of the presidents of student councils in the Board of Regents of all state colleges and universities.^[11][14][15] During her term, she was the chairperson of the Senate Committee on Games, Amusements, and Tourism, as well as the Senate Committee on National Minorities.^[12]

Second term and martial law

Relations between Kalaw and the ruling Nacionalista Party were uneasy under the Marcos administration. The increasing authoritarianism of the Marcos government led Kalaw to become one of the few people within the party to criticize the administration. By 1971, convinced that the party will not include her in the senatorial slate for the upcoming elections, Kalaw decided to accept the offer from her cousin, opposition senator Benigno Aquino Jr., to become guest candidate of the Liberal Party.^[8] During the party's miting de avance at Plaza Miranda in Quiapo, Manila on August 21, 1971, Kalaw was among the senatorial candidates present when an unidentified assailant threw two hand grenades at the stage. She wasn't seriously injured, but fellow party members such as Senator Jovito Salonga, Manila mayoralty candidate Ramon Bagatsing and Manila city councilor Ambrosio Lorenzo Jr. were among those seriously harmed. On election day, however, Kalaw, together with five other Liberal Party senatorial candidates—Jovito Salonga, Genaro Magsaysay, John Henry Osmeña, Eddie Ilarde and Ramon Mitra Jr.—won six out of eight Senate seats.^[16] She was the first-ever female Filipino senator to win two consecutive terms.^[9][12]

Since the Plaza Miranda incident, Kalaw dedicated her second term to becoming full-time opposition to President Marcos. However, Marcos' declaration of Martial Law and abolition of Congress cut short her term. Nevertheless, she continued in her activism in opposition of Martial Law, resulting in her imprisonment at Fort Bonifacio twice, including one in 1979 for allegedly participating in a coup attempt against Marcos.^{[5][9][11][12]}

Assemblywoman of Manila

Following her release from prison, Kalaw worked to unite a fragmented opposition by bringing together the remnants of the Liberal and Nacionalista parties to form United Nationalist Democratic Organization (UNIDO), which would serve as the main opposition party against Marcos' Kilusang Bagong Lipunan. The assassination of opposition figure Benigno Aquino Jr. on August 21, 1983 further emboldened the opposition parties to fight Marcos, and in 1984, Kalaw ran as assemblywoman and won one of six seats in the Regular Batasang Pambansa for Manila. She was joined by fellow UNIDO assemblymen Jose Atienza Jr., Carlos Fernando, Gemiliano Lopez Jr. and Gonzalo Puyat II who occupied four of the remaining seats (the last seat going to KBL candidate Arturo Tolentino).^[8][9][12]

Vice presidential bid

In November 1985, President Marcos called for a snap presidential election in order to convince the American government that he is still in control of the Philippines amid the economic crisis that affected the country since the assassination of Aquino. Kalaw, along with Senator Salvador Laurel, were among the opposition members who expressed their intention to run for president. However, majority of UNIDO members preferred Aquino's widow Corazon Aquino as the party's official presidential candidate. Both Laurel and Kalaw decided to give in to Aquino after nationwide signature campaign gathered more than a million signatures urging Aquino to run for president. In her choice of vice president, however, Aquino chose Laurel over Kalaw, who decided to unsuccessfully run as a third vice presidential candidate under the Kalaw-wing of the Liberal Party. However, the snap elections on February 7, 1986 were mired with allegations of rampant fraud by the government, and the tandem of Aquino and Laurel came to power as president and vice president respectively after a peaceful People Power Revolution from February 23–25, 1986 that toppled the Marcos regime.^{[5][8][9][12]}

Post-EDSA Revolution

After the People Power Revolution, Kalaw joined the opposition against Corazon Aquino's administration. She was among the few UNIDO members who joined the Grand Alliance for Democracy, a coalition party that consisted mostly of defectors from Marcos' Kilusang Bagong Lipunan, Nacionalista Party and the UNIDO. She was one of GAD's senatorial candidates during the 1987 Senatorial Elections but lost.^[9][11][12] In 1992, Kalaw was reunited with former Vice President Laurel, and the two ran together as the Nacionalista Party's candidates for President and Vice President during the 1992 Philippine presidential elections,^{[lower-alpha 1]} but they both lost to Aquino's Defense Secretary Fidel V. Ramos and former actor and Senator Joseph Estrada.^[9][11][12]

Kalaw's last foray in public service was her appointment as managing director and resident representative of the Philippines at the Manila Economic and Cultural Office, the country's de facto embassy in Taipei, Taiwan during the Ramos and Estrada administrations.^[11][12]