In 1937 Pike went to the University of Michigan, where he worked for his doctorate in linguistics under Edward Sapir. His research involved living among the Mixtecs, and he and his wife Evelyn developed a written system for the Mixtec language. After gaining his Ph. D. In 1942, Pike became president of Summer Institute in Linguistics (SIL). The Institute's main function was to produce translations of the Judæo-Christian Bible into unwritten languages, and in 1951 Pike published the Mixtec New Testament. He was the President of SIL International from 1942 to 1979.
As well as and in parallel with his role at SIL, Pike spent thirty years at the University of Michigan, during which time he served as chairman of its linguistics department, professor of linguistics, and director of its English Language Institute (he did pioneering work in the field of English language learning and teaching) and was later Professor Emeritus of the university.
He was a member of National Academy of Sciences, the Linguistic Society of America (LSA), the Linguistic Association of Canada and the United States (LACUS), and the American Anthropological Association. He served as president of LSA and LACUS.
Pike developed his theory of tagmemics to help with the analysis of languages from Central and South America, by identifying (using both semantic and syntactic elements) strings of linguistic elements capable of playing a number of different roles.
Pike's approach to the study of language put him outside the circle of the "generative" movement begun by Noam Chomsky, a dominant linguist, since Pike believed that the structure of language should be studied in context, not just single sentences, as seen in the title of his magnum opus "Language in relation to a unified theory of the structure of human behavior" (1967).
He became well known for his "monolingual demonstrations". He would stand before an audience, with a large number of chalkboards. A speaker of a language unknown to him would be brought in to work with Pike. Using gestures and objects, not asking questions in a language that the person might know, Pike would begin to analyze the language before the audience.
When asked whether he was a missionary or a linguist, he replied "I am a mule." He explained that a mule is part horse, part donkey, combining traits of each. He pointed out that sometimes he did more of the work of a horse, other times he did more of the work of a donkey, but he was always both (Headland 2001:508).