Both targeted and genome-wide studies have revealed genetic associations for susceptibility, prognosis, and treatment-induced secondary malignancies and toxicities in classical Hodgkin lymphoma (cHL). This review gives a systematic and comprehensive overview of significant associations and places them into a biologic context. The strongest susceptibility polymorphisms have been found for the human leukocyte antigen (HLA) genes. These associations are specific for cHL overall or for subgroups based on tumor cell Epstein-Barr virus (EBV) status. These findings strongly suggest that EBV-specific immune responses influence cHL susceptibility in EBV+ cHL and that immune responses targeting other tumor-associated antigens are important in EBV- cHL. Accordingly, most of the numerous other susceptibility loci map to genes that affect functionality of the immune system, underscoring the crucial role of the immune system in cHL development. The number of association studies on cHL prognosis is limited with one consistent association for the drug-metabolizing UGT1A1 gene. PRDM1 is associated with radiation-induced secondary malignancies and a small number of genes are associated with treatment-related toxicities. In conclusion, most loci showing genetic associations in cHL harbor genes with a potential functional relevance for cHL susceptibility. (C) 2014 AACR.