The Research Center for Language and Semiotic Studies at Indiana University (IU) had its origin in Herman B Wells' creation of the Research Center for Anthropology, Folklore, and Linguistics in 1955. Distinguished Professor of English and Folklore Stith Thompson was initially appointed its chairperson, but his retirement from teaching and concurrent work for a 1956-1957 Guggenheim Fellowship rendered him unable to lead the Center during its early formation. Wells subsequently offered the chair to Thomas A. Sebeok, then-Associate Professor of English and Linguistics, due to his interdisciplinary research interests and managerial talent for attracting external research funds. Sebeok acted as chairperson for the Center from 1956 until his retirement in 1991.

The Research Center for Anthropology, Folklore, and Linguistics was initially charged with the coordination of research and scholarly communications across several archival collections on campus, including the Archives of Traditional Music and the then-named Archives of Folklore (the latter collection is now known as the IU Folklore Archives). Over the course of the Center's first decade, Sebeok worked to redistribute these heavily used research collections among other campus units such as the Folklore Institute. This allowed the Center to expand its Research Associates program, which sponsored postdoctorate scholars on campus and from around the world through the duration of its activities.

In 1964 the Center oversaw the Linguistic Society of America's summer Linguistic Institute; the eight-week-long gathering at IU brought together around 70 scholars from across the world to lead lectures and courses in traditional subfields of linguistics (such as historical, comparative, descriptive, and applied), critical theoretical approaches to linguistics, computational linguistics, and a range of related subjects in the humanities. The Institute led to an outpouring of significant scholarship in and beyond these disciplines. By the mid-1960s, the Center had established a global reputation as the central node for scholarly activity at the intersections of language sciences, anthropology, and the humanities. As Chairperson, Sebeok brought together these disciplines under the banner of semiotics and became one of the most significant contributors to semiotic studies.

In 1968 the Center founded its own periodical, Language Sciences, which it published in-house until 1978. Other major editorial activities during this time included the preparation of Current Trends in Linguistics, an encyclopedia published in 14 volumes between 1963-1976; the coordinated oversight of the International Association of Semiotic Studies' periodical, Semiotica, beginning in 1969; and the creation of a reading list in linguistics, commissioned by the National Endowment for the Humanities in 1972.

The Center progressed through several significant administrative transformations over the course of the 1960s-1970s. In 1967 the IU Board of Trustees approved a change in name from the Research Center for Anthropology, Folklore, and Linguistics to the Research Center for Language Sciences. The Center changed names again in 1975, becoming the Research Center for Language and Semiotic Studies (RCLSS). This remained the Center's title for the duration of its administration. Starting in 1969, a six-member Visiting Committee continually evaluated the Center's performance and reported to the IU Office of the Vice President. Committee members represented private foundations such as the MacArthur Foundation, public institutions such as the Smithsonian Institution and the National Humanities Center, scholarly federations such as the American Council of Learned Societies, and external academic departments.

Over the course of the 1970s-1990s, RCLSS established a notable instructional role on campus. It began offering courses as early as 1975 through the Departments of Linguistics, Anthropology, Comparative Literature, and others in the College of Arts and Sciences and Hutton Honors College. In 1978 the University Graduate School approved a doctoral minor in Semiotic Studies, and in 1981 the Board of Trustees approved RCLSS' proposal for an undergraduate Certificate in Semiotic Studies. Courses in Semiotic Studies and the Ph.D. minor were offered through at least the 2000-2002 academic year. The research and publishing activities of the Center, however, declined following Sebeok's retirement in 1991.