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Krishnamurthy was born at Puttamangalam near Mayiladuthurai in the old Thanjavur district in an orthodox, large Brahmin family with limited means. After primary education in the village, Krishnamurthy joined the National High School at Tiruchi, about 100 kilometres away.

When Mahatma Gandhi launched his non-cooperation movement in 1921, thousands of students gave up their studies to participate; Krishnamurthy was among them. Inspired by Gandhi's speech at a public meeting in Tiruchi, and despite the Secondary School Leaving Certificate examination being just three months away, he left school and joined the Indian National Congress.

In 1922, he was given a one-year prison sentence for participating in the independence struggle. It was during this period that Krishnamurthy came into contact with two people who were to play a major role throughout his life: veteran Congress leader C. Rajagopalachari, and T.Sadasivam, who was to become a life-long friend and partner in journalistic ventures.

Krishnamurthy's first attempt at writing fiction also came during that period. In 1923 he became a sub-editor on Navasakthi, a Tamil periodical edited by Tamil scholar and freedom fighter V. Kalyanasundaram, known as "Thiru Vi. Ka". Krishnamurthy's first book was published in 1927.

Leaving Navasakthi in 1928, Krishnamurthy stayed with C. Rajagopalachari at the Gandhi Ashram in Tiruchengode in Salem district and helped him edit Vimochanam, a Tamil journal devoted to propagating prohibition. In 1931, he was again imprisoned for six months.

Next year Krishnamurthy joined Ananda Vikatan, a weekly edited and published by S. S. Vasan, as its de facto editor. The magazine soon became a household name in middle class families. Krishnamurthy's witty, incisive comments on politics, literature, music and other forms of art were looked forward to with unceasing interest by readers. He wrote under the pen names of "Kalki", "Ra. Ki", "Tamil Theni", "Karnatakam" ,and so on. Vikatan published many of his short stories and novels (as serials).

The name Kalki denotes the impending tenth Avatar of Lord Vishnu in the Hindu religion, who it is said, will bring to an end the Kali Yuga and reinstate Dharma or righteoueness among the worldly beings. He used the name because like the Avatar he wanted to bring about great changes, and also in honor of his mentor Kalyana Sundaram Mudaliar, taking the "Kal" from his name and the "Ki" from his own. He is often referred to as "Kalki Krishnamurthy" or simply "Kalki".

In 1941 he left Ananda Vikatan and rejoined the freedom struggle and courted arrest. On his release after three months he and Sadasivam started the weekly, Kalki. He was its editor until his death on December 5, 1954. In 1956, he was awarded the Sahitya Akademi Award posthumously for his novel Alai Osai.