Despite the introduction of targeted agents leading to therapeutic advances, clinical management of patients with metastatic colorectal cancer (mCRC) is still challenged by significant interindividual variability in treatment outcomes, both in terms of toxicity and therapy efficacy. The study of germline genetic variants could help to personalize and optimize therapeutic approaches in mCRC. A systematic review of pharmacogenetic studies in mCRC patients published on PubMed between 2011 and 2021, evaluating the role of germline variants as predictive markers of toxicity and efficacy of drugs currently approved for treatment of mCRC, was perfomed. Despite the large amount of pharmacogenetic data published to date, only a few genetic markers (i.e. DPYD and UGT1A1 variants) reached the clinical practice, mainly to prevent the toxic effects of chemotherapy. The large heterogeneity of available studies represents the major limitation in comparing results and identifying potential markers for clinical use, the role of which remains exploratory in most cases. However, the available published findings are an important starting point for future investigations. They highlighted new promising pharmacogenetic markers within the network of inflammatory and immune response signaling. In addition, the emerging role of previously overlooked rare variants has been pointed out.