Therapeutic strategies that block Cytotoxic T lymphocyte antigen-4 (CTLA-4) enhance antitumor immunity and prolong the lives of patients with metastatic melanoma. However, only a subset of patients benefit, and responses are often delayed due to heterogeneous response kinetics. Ongoing monitoring of the immunologic effects of therapy and correlating these immunologic changes with patient outcomes continue to be important goals to better identify possible mechanisms of clinical activity of these agents. This chapter introduces the major areas of investigation in monitoring patients treated with CTLA-4 blockade and provides specific details of our experience performing selected assays.