This chapter discusses topics in the design of clinical trials for Multiple Sclerosis. This nontechnical discussion introduces concepts such as phases of trials, basic design strategies and the importance of the question at hand and the outcomes. The chapter discusses the concept of Bayesian statistical design versus Frequentist approaches. A host of modern designs ranging from adaptive designs to treatment paradigms to targeted designs are introduced. Strategies for treatment selection, randomized withdrawal designs and futility designs are covered. Finally how to evaluate multiple drugs in an era of limited placebo controlled trials are discussed and the chapter ends with the competing demands of the shortest trials to get efficacy answers for immediate goals versus the value of long term studies for future outcomes and long term safety. © 2014 Elsevier B.V.