A critical link exists between an individual's ability to repair cellular DNA damage and cancer development, progression, and response to therapy. Knowledge gained about the proteins involved and types of damage repaired by the individual DNA repair pathways has led to the development of a variety of assays aimed at determining an individual's DNA repair capacity. These assays and their use in the analysis of clinical samples have yielded useful though somewhat conflicting data. In this review article, we discuss the major DNA repair pathways, the proteins and genes required for each, assays used to analyze activity, and the relevant clinical studies to date. With the recent results from clinical trials targeting specific DNA repair proteins for the treatment of cancer, accurate, reproducible, and relevant analysis of DNA repair takes on an even greater significance. We highlight the strengths and limitations of these DNA repair studies and assays, with respect to the clinical assessment of DNA repair capacity to determine cancer development and response to therapy.