Multiple sclerosis (MS) is a complex and unpredictable neurological condition. It is the most commonly seen autoimmune disorder. The incidence of disease and its prevalence are growing worldwide. Early identification of the disease and accurate diagnosis is important to prevent further complications and disability. The etiology remains unclear, and it is believed that complex gene-environment interactions play an essential role. Genetic predisposition only describes a portion of the disease risk, whereas lifestyle and environmental factors are significant contributors. Smoking was identified as an important risk factor for MS. The main objectives of this review were to examine the underlying mechanisms of immune dysregulation in the development of MS, explore the association between smoking and MS, and identify other genetic and environmental factors that alter the risk of developing the disease. We searched PubMed for articles relevant to the study topic published between 2000 and 2020 using the search terms "multiple sclerosis," "cigarette smoking," "risk factors," and, "epigenetics." Studies reveal a marked association between smoking and the risk of MS. Unlike genetic risk factors, many lifestyles and environmental factors can be adjusted, with potential for prevention, particularly for people at the highest risk, such as families of individuals with MS.