Thorough annotation of common germline genetic variation in the human genome has generated a foundation for the investigation of the contribution of genetics to the etiology and pathogenesis of cancer. For many malignancies, it has become increasingly apparent that numerous alleles, with small-to-moderate effects, additively contribute to cancer susceptibility. The most common genetic variant in the genome, the single nucleotide polymorphism, is of special interest for the study of susceptibility to and protection from cancer. Similarly, intense effort has focused on genetic variants that can predict either response or toxicity to therapeutic interventions. This review discusses the challenges and prospects of genetic association studies in cancer research. On the basis of recent changes in genomics and high-throughput genotyping platforms, future genetic findings of association studies could impact clinical care and public health screening.