Immunotherapeutic approaches for melanoma and other cancers can impart profound clinical benefit but only for a subset of patients. Interpatient heterogeneity could, in principle, be due to somatic differences in the tumor between individuals or alternatively be accounted for distinct germline polymorphisms in immunoregulatory genes of the host. Analysis of these possibilities has been initiated by investigating gene expression profiling of the tumor microenvironment in the context of clinical trials of cancer vaccines. Distinct gene expression profiles have been identified on pretreatment biopsies that are associated with a positive or negative clinical outcome. These observations suggest that such profiling might be useful as a predictive biomarker for clinical benefit from vaccines and other immunotherapy approaches, and analysis of specific gene products has begun to suggest new therapeutic interventions to overcome mechanisms of tumor resistance.