Extracellular heat shock proteins (HSP) play important roles in cell signaling and immunity. Many of these effects are mediated by cell surface receptors expressed on a wide range of cell types. We have investigated the nature of such proteins by cloning candidate receptors into cells (CHO-K1) with the rare property of being null for HSP binding. Using this approach, we have discovered that Hsp70 binds to a least two classes of receptor: c-type lectin receptors (CLR) and scavenger receptors (SR). However, the nature of the receptor-ligand interactions is not yet clear. Hsp70 can bind to LOX-1 (a member of both the CLR and SR), with the c-type lectin binding domain (CTLD) as well as the SR family members SREC-I and FEEL-1/CLEVER-1/STABILIN-1, which by contrast have arrays of EGF-like repeats in their extracellular domains. In this chapter, we discuss (1) methods for determining HSP receptors, (2) approaches to study of individual receptors in cells that contain multiple such receptors, and (3) methods for investigating HSP receptor function in vivo.