Chiang was an influential member of the Nationalist Party, the Kuomintang (KMT), and was a close ally of Sun Yat-sen. He became the Commandant of the Kuomintang's Whampoa Military Academy, and took Sun's place as leader of the KMT when Sun died in 1925. In 1926, Chiang led the Northern Expedition to unify the country, becoming China's nominal leader. He served as Chairman of the National Military Council of the Nationalist government of the Republic of China (ROC) from 1928 to 1948.

Chiang led China in the Second Sino-Japanese War, during which the Nationalist government's power severely weakened, but his prominence grew. Unlike Sun Yat-sen, Chiang Kai-shek was socially conservative, promoting traditional Chinese culture in the New Life Movement and rejecting western democracy and the nationalist democratic socialism that Sun Yat-sen and some other members of the KMT embraced in favor of a nationalist authoritarian government.

Chiang's predecessor, Sun Yat-sen, was well-liked and respected by the Communists, but after Sun's death Chiang was not able to maintain good relations with the Communists. A major split between the Nationalists and Communists occurred in 1927; and, under Chiang's leadership, the Nationalists fought a nation-wide civil war against the Communist Party of China (CPC). After Japan invaded China in 1937, Chiang agreed to a temporary truce with the CPC. Despite some early cooperative military successes against Japan, by the time that the Japanese surrendered in 1945 neither the CPC nor the KMT trusted each other or were actively cooperating.

After American-sponsored attempts to negotiate a coalition government failed in 1946, the Chinese Civil War resumed. The CPC defeated the Nationalists in 1949, forcing Chiang's government to retreat to Taiwan, where Chiang imposed martial law and persecuted people critical of his rule in a period known as the "White Terror". After evacuating to Taiwan, Chiang's government continued to declare its intention to retake mainland China. Chiang ruled the island securely as the self-appointed President of the Republic of China and Director-General of the Kuomintang until his death in 1975.