Upon completing her dissertation in 1976, Lindquist moved to the University of Chicago for a short post-doc before being hired as a faculty member in the Biology Department in 1978, becoming the Albert D. Lasker Professor of Medical Sciences with the founding of the Department of Molecular Genetics and Cell Biology in 1980. At the University of Chicago Lindquist investigated the role of heat shock proteins in regulating the cellular response to environmental stresses. Lindquist pioneered the use of yeast as a model system to study how heat shock proteins regulate gene expression and protein folding. For this work, Lindquist was made an investigator for the Howard Hughes Medical Institute in 1988. After making important new discoveries to prions, Lindquist moved to MIT in 2001 and was appointed as Director of the Whitehead Institute for Biomedical Research, one of the first women in the nation to lead a major independent research organization.