The development of new genomic technologies has led to an exponential increase in the number of biomarkers for drug safety and efficacy. Pharmacogenomics has the potential to impact clinically relevant outcomes in drug dosing, efficacy, toxicity, and prediction of adverse drug reactions (ADRs). Genotype-based prescribing is anticipated to improve the overall efficacy rates and minimize ADRs, making personalized medicine a reality. Genome-wide association studies have been increasingly applied to pharmacogenetics. Severe ADRs are a major issue for drug therapy because they can cause serious disorders and can be life threatening. For severe ADRs, significant associations have been reported for drug-induced liver injury, statin-induced myopathy, increased risk of hemorrhagic complications of anticoagulant use, drug-induced torsade de pointes, drug-induced long QT, and severe cutaneous ADRs. This review summarizes the current position concerning the clinical and pharmacoepidemiological relevance of pharmacogenetic biomarkers in ADR prediction and prevention, with an emphasis on genetic risk factors and biomarkers for three specific severe ADRs.