Multicellular organisms are composed of distinct cells and tissues that coordinate highly orchestrated responses to environmental challenges, including those that arise with age. Since C. elegans is a premier model system used to study the molecular and cellular regulators of adult and aging phenotypes, cell type- and tissue-specific approaches are needed to characterize the genome-wide expression changes associated with these responses. Here we describe a method for the FACS-based isolation and RNA sequencing of dissociated cells from adult C. elegans. This technique is amenable to profiling the cell- and tissue-specific gene expression changes in C. elegans mutants, including aging models, such as the daf-2/insulin-like signaling (IIS) pathway, and in wild-type animals with age.