Multiple sclerosis is a complex, heterogeneous disease associated with long-term disability. Despite the availability of advanced disease-modifying and symptomatic therapies that may decrease activity and progression of disease and alleviate complaints to a certain extent, there is still a need for comprehensive rehabilitation interventions in order to reduce sequels and symptoms of the disease on personal activities and social participation to achieve the highest possible independence and the best quality of life. Timing and setting of rehabilitation interventions should be selected individually depending on disease phase, functional deficits, personal requirements, as well as specific goals. In addition, limitations and disease-specific characteristics that may influence rehabilitation outcome should be noted. Rehabilitation interventions should be considered early for maintaining functional capacity and reducing risk for losing important abilities or independence. Due to gradual failure of adaptive compensatory mechanisms along the course of disease, benefits of rehabilitation interventions are generally higher in earlier phases of MS. Inpatient and outpatient multidisciplinary rehabilitation has been shown to be beneficial in improving disability, participation and quality of life despite progression of the disease. Good evidence exists for different specific interventions improving physical and cognitive performance. Other important issues responsible for beneficial effects of comprehensive rehabilitation in MS include education, instruction, and information of patients and caregivers. Comprehensive assessment of health domains in MS patients using standardized framework and common language for describing the impact of disease at different levels, using International Classification of Functioning, Disability and Health (ICF) core sets may increase the knowledge of needs of these patients for more efficient and adapted rehabilitation interventions meeting these individual requirements, and promote perception and acceptance of rehabilitation as a valuable treatment option in MS. ICF core sets may increase the knowledge of more efficient and adapted rehabilitation measures meeting more properly individual requirements, and promote perception and acceptance of rehabilitation as a valuable treatment option in MS.