Background: Over the past two decades, various novel disease-modifying drugs for multiple sclerosis (MS) have been approved. However, there is high variability in the patient response to the available medications, which is hypothesized to be partly attributed to genetics. Objectives: To conduct a systematic review of the current literature on the pharmacogenomics of MS therapy. Methods: A systematic literature search was conducted using PubMed/MEDLINE database searching for articles investigating a role of genetic variation in response to disease-modifying MS treatments, published in the English language up to October 9th, 2018. PRISMA guidelines for systematic reviews were applied. Studies were included if they investigated response or nonresponse to MS treatment defined as relapse rate, by expanded disability status scale score or based on magnetic resonance imaging. The following data were extracted: first author's last name, year of publication, PMID number, sample size, ethnicity of patients, method, genes, and polymorphisms tested, outcome, significant associations with corresponding P-values and confidence intervals, response criteria, and duration of the follow-up period. Results: Overall, 48 articles published up to October 2018, evaluating response to interferon-beta, glatiramer acetate, mitoxantrone, and natalizumab, met our inclusion criteria and were included in this review. Among those, we identified 42 (87.5%) candidate gene studies and 6 (12.5%) genome-wide association studies. Existing pharmacogenomic evidence is mainly based on the results of individual studies, or on results of multiple studies, which often lack consistency. In recent years, hypothesis-free approaches identified novel candidate genes that remain to be validated. Various study designs, including the definition of clinical response, duration of the follow-up period, and methodology as well as moderate sample sizes, likely contributed to discordances between studies. However, some of the significant associations were identified in the same genes, or in the genes involved in the same biological pathways. Conclusions: At the moment, there is no available clinically actionable pharmacogenomic biomarker that would enable more personalized treatment of MS. More large-scale studies with uniform design are needed to identify novel and validate existing pharmacogenomics findings. Furthermore, studies investigating associations between rare variants and treatment response in MS patients, using next-generation sequencing technologies are warranted.