The development of new anti-myeloma agents with different mechanisms of action from conventional chemotherapy has necessitated a new look at clinical trial design. We discuss design issues for cytostatic agents for phase I, II, and III clinical trials pertaining to myeloma. The success of phase I trials with cytotoxic agents is predicated on the dose toxicity curve being strictly monotone. With cytostatic agents, however, the shape of the dose toxicity curve is not necessarily monotone, and traditional phase I trial designs may no longer be applicable. The distinction between cytotoxic and cytostatic agents also highlights the importance of thinking of endpoints other than tumor response (or shrinkage) with agents whose success depends more on keeping the tumor stable. The appropriateness of different endpoints in phase II myeloma trials is discussed. The goal of phase III clinical trials for cytostatic agents is typically twofold: to determine efficacy of the new agent for all patients and for the subset of patients with a certain biomarker. We present different trial designs that can address both aims.