Multiple sclerosis (MS) has a profound impact on health-related quality of life (HRQoL), a comprehensive subjective measure of the patient's health status. Assessment of HRQoL informs on the potential advantages and disadvantages of disease-modifying drugs (DMDs) beyond their effects on observer-based disability and magnetic resonance imaging abnormalities. This article reviews published data from randomized controlled trials and observational studies regarding the effects of currently available DMDs on HRQoL. Data indicate that DMD treatment is associated with prevention of worsening or with improvement of HRQoL, and that, in general, second-line DMDs may have a greater impact on HRQoL than first-line DMDs. In clinical practice, monitoring of HRQoL provides clinicians with unique information regarding disease impact and potential benefits and adverse effects of DMD treatment that may not be obtained otherwise; it might also permit early detection of an unfavorable disease course. It is suggested to assess HRQoL at the time of diagnosis and before starting or switching DMD treatment. Regular HRQoL measurements contribute to a comprehensive clinical evaluation, and may help to elucidate and quantify the patient's contribution to shared decision making regarding DMD treatment. Further studies are needed to better determine the role of HRQoL assessments in daily MS care.