We have come to recognize in recent years that our patients’ comorbid conditions are extremely important to the optimal management of MS. Comorbid conditions may impact virtually every aspect of MS, including time to diagnosis, MS disease activity, treatment persistence, and mortality. A Danish group analyzed data from nearly 9000 patients with incident MS and found that patients with cerebrovascular, cardiovascular, lung, diabetes, and cancer comorbidities experienced significantly greater delays in time to diagnosis than comparators. Diagnostic delays in patients with multiple comorbidities are not surprising, as it can take longer to trace the patient’s problems to MS; still, the repercussions of these delays are significant. We try to identify MS quickly and initiate the appropriate treatment as soon as possible to minimize permanent damage to the central nervous system. Comorbidity can also impact mortality, and multiple studies show that patients with MS have shorter life spans in the context of comorbid vascular disease, lung disease, diabetes, Parkinson disease, and cancer, as well as psychiatric comorbidity (principally anxiety and/or depression). Moreover, these highly prevalent comorbidities have been tied to MS disease activity. A 2017 Canadian study of 885 patients with relapsing MS, for instance, revealed that approximately 40% had anxiety, approximately 21% had depression, nearly 18% had hypertension, approximately 18% had migraine, and nearly 12% had hyperlipidemia, and that those with migraine, hyperlipidemia, or 3 or more conditions had an increased relapse rate over 2 years. A 2017 Italian study suggests that comorbid illness may also impact a patient’s ability to persist with the initially prescribed disease-modifying therapy (DMT). Of approximately 2000 newly diagnosed patients, nearly 24% had at least 1 comorbidity that compromised their ability to tolerate their first DMT (in this case, mainly interferon beta). That study highlights not only the significant rate of comorbid conditions in early MS—a much higher rate than might be expected—but also the significant impact of comorbidity on the ability to tolerate or persist with the initial DMT. Major comorbid conditions of concern in MS also include autoimmune disorders, cancer—especially cervical, breast, and gastrointestinal tract cancers—lung disease, and epilepsy. The most recent American Academy of Neurology practice guideline reflects the growing evidence, specifically stating that comorbid conditions worsen MS outcomes and that it is important to counsel our patients about these conditions.