Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for the stability and function of multiple mutated, chimeric and over‐expressed signaling proteins that promote the growth and/or survival of cancer cells. Hsp90 client proteins include mutated p53, Bcr‐Abl, Raf‐1, Akt, HER2/Neu (ErbB2) and HIF‐1α. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the destabilization and eventual degradation of Hsp90 client proteins, and the first‐in‐class Hsp90 inhibitor, 17‐allylamino‐17 demethoxygeldanamycin (17AAG), is currently in phase II clinical trials. A fraction of Hsp90 has been identified at the cell surface and its presence has recently been shown to correlate with melanoma progression. Inhibition of cell‐surface Hsp90 with antibodies or cell‐impermeable Hsp90 inhibitors blocks cell motility and invasion in vitro and cancer metastasis in vivo. Thus, cell‐surface Hsp90 may play a unique role in tumor metastasis, distinct from but perhaps overlapping with its intracellular function. In addition, because cell‐surface Hsp90 may be the point of contact between some viruses and host cells, this pool of the chaperone may play a distinct role in initiation of infectious disease. (Cancer Sci 2007; 98: 1536–1539)