When introduced in the early and middle 1990s, current first-line pharmacologic therapies for multiple sclerosis (MS)--interferon beta-1a, interferon beta-1b, and glatiramer acetate--constituted a major advancement in MS treatment. Nevertheless, disease progression, although typically delayed with these agents, remains inevitable in most patients and constitutes a significant limitation of the currently available treatments. Moreover, the first-line therapies all require frequent subcutaneous or intramuscular injections, delivery modalities that are associated with subpar treatment adherence. The demand for more effective agents has produced a new generation of MS therapies with impressive efficacy profiles--although their long-term safety and tolerability remain largely unknown. Some of the new agents have been formulated for oral administration, which will likely have a positive impact on treatment adherence. These new agents are appearing during a time of major change in MS research. As the old expectation of inevitable disease progression is being reconsidered, the notion of sustained disease inactivity has become a credible, still somewhat elusive, goal. Neuroprotection may also be possible with new and existing treatments. At the same time, new imaging techniques, such as measuring disease progression via T1-hypointense lesions ("black holes"), and a better understanding of pathophysiologic factors in MS--such as the role of neurotrophic growth factors and oxidative stress--are changing the ways that efficacy is measured and how new agents are developed.