The success of immunotherapeutics over the past decade has fundamentally altered the therapeutic landscape in melanoma and non-small cell lung (NSCLC) cancer care. Multiple clinical trials have confirmed significant improvements in survival with a variety of immunotherapeutic strategies. The careful and appropriate selection of standard of care (SOC) therapies is key to the successful design and interpretation of these trials. To date immunotherapeutic trials have used best supportive care, matched placebo, chemotherapy, targeted therapy or, more recently, established immunotherapeutics in melanoma clinical trials as SOCs. Each of these SOC choices has a fundamental impact on the selection and validity of response assessment criteria and clinical endpoints. As yet there is no established approach, thus new data must be interpreted with an understanding of the limitations of the current paradigm. Additionally, the pace of development has mandated the use of novel clinical trial designs, answering multiple therapeutic questions simultaneously and designed to expedite regulatory approval. This review addresses the most important challenges in the selection of SOC in immunotherapeutic trials and the current and future challenges in trial design.