Heat-shock proteins (HSPs) serve as both a valuable target as well as a potent tool in the therapy of melanoma and human papillomavirus infections. HSPs have been found to associate with key pathogenic antigens and, under different circumstances, activate or suppress both innate and adaptive immunity via several mechanisms. The dominant mechanism of HSP is as a chaperonin to upregulate antigens on antigen-presenting cell surfaces. While no HSP-based therapies are currently FDA approved, several are currently in phase III clinical trials. This study reviews the current literature on therapeutic studies of HSP and the significant role these proteins are likely to play in future therapeutic approaches to neoplasms, infections, and inflammatory diseases of the skin.