The basic pathologic hallmark of multiple sclerosis is inflammation, but the causal factors involved in the formation of confluent plaques of demyelination and neurodegeneration in the brain, as well as loss of brain volume, have been difficult to elucidate. Efforts to identify downstream sequences leading to demyelination have resulted in the development of newer pharmacologic agents, but the larger questions are if, in the clinic, these agents are 1) really effective; and 2) focusing on the right targets?