Most efforts aimed at understanding the notable heterogeneity of outcomes in multiple sclerosis (MS) have focused on disease-specific factors, such as symptoms at initial presentation, initial relapse rate, and age at symptom onset. These factors, however, explain relatively little of the heterogeneity of disease outcomes. Owing to the high prevalence of comorbidity in MS and the potential for its prevention or treatment, comorbidity is of rising interest as a factor that could explain the heterogeneity of outcomes. A rapidly growing body of evidence suggests that comorbidity adversely affects outcomes throughout the disease course in MS, including diagnostic delays from symptom onset, disability at diagnosis and subsequent progression, cognition, mortality, and health-related quality of life. Therefore, clinicians need to incorporate the prevention and management of comorbidity when treating patients with MS, but managing comorbidities in MS successfully may require the adoption of new collaborative models of care.