As the prevalence and functional consequences of multiple sclerosis (MS)-related cognitive dysfunction became more widely recognized, several definitive trials of disease-modifying medications for relapsing remitting MS and progressive MS incorporated neuropsychological (NP) outcome measures. This chapter lists clinical trials designed to assess the efficacy of medications as symptomatic treatment for cognitive impairment. Several factors complicate the assessment of NP outcomes in MS trials, although none is insurmountable. With the recent development of functional magnetic resonance imaging (fMRI), it has been possible to image MS patients while they perform cognitive tests in the scanner. In general, these fMRI studies have demonstrated that, even when cognitive testing is comparable to healthy controls, MS patients exhibit a larger number of activated regions, an increase in MR signal change and spatial extent in regions also activated by controls, and a decrease in laterality indices.