STS-1 and STS-2 form a small family of proteins that are involved in the regulation of signal transduction by protein–tyrosine kinases. Both proteins are composed of a UBA domain, an esterase domain, an SH3 domain, and a PGM domain. They use their UBA and SH3 domains to modify or rearrange protein–protein interactions and their PGM domain to catalyze protein–tyrosine dephosphorylation. In this manuscript, we discuss the various proteins that have been found to interact with STS-1 or STS-2 and describe the experiments used to uncover their interactions.