In the past 5 years, the treatment of metastatic melanoma has changed from almost no effective treatment to the use of targeted and immune therapies with proven improvements in survival. The time has now come to define the optimal drug combinations, sequence of treatment, and drug regimens (intermittent vs continuous dosing) in the treatment of patients with metastatic melanoma. In view of the prevalence of advanced melanoma, finite resources, and the heterogeneity of disease characteristics, not all possibilities can be tested in therapeutic trials starting from an unselected population of patients with metastatic melanoma. In practice, clinicians rely on a few clinically derived signals, especially dynamic signals, to categorise patients into scenarios, from fast disease kinetics to slow disease kinetics, which drive clinicians' therapeutic decision making. The realistic goals of therapy are different in each scenario. We recommend that these scenarios are incorporated into clinical trials as either patient inclusion criteria or stratification factors. This approach is not only feasible but is also the only way to generate evidence for more effective and individualised treatment strategies for patients with metastatic melanoma.