This review summarizes a number of key approaches to novel designs in multiple sclerosis clinical trials. The concept of the novel design is discussed, and the interplay between design decisions and trial end points is debated. We provide reminders that there are trade-offs between the end points chosen and the type of design. The opportunity for more novel designs resides in Phase II studies, and several types of novel designs are discussed, including: adaptive designs, Bayesian design, treatment strategy designs and futility designs. The fact is that the end points in multiple sclerosis still exert a limiting effect on the designs, and underscore the need for long-term follow-up information compared with short-term information. Overall, the design is only as good as the underlying question and the end points chosen to evaluate it. © 2008 Future Medicine Ltd.