DNA damage repair (DDR) pathways modulate cancer risk, progression and therapeutic response. We systematically analyzed somatic alterations across 33 cancer types in order to provide a comprehensive view of DDR deficiency in cancer. Mutations with accompanying loss-of-heterozygosity were observed in over 1/3 of DDR genes including TP53 and BRCA1/2. Additional prevalent alterations, e.g. EXO5, MGMT and ALKBH3 silencing, were identified in ~20% of samples. Newly generated Homologous Recombination Deficiency (HRD) scores demonstrated that many cancer types had varying fractions of samples with high HRD scores, most prevalent in but not limited to ovarian cancer. Protein structure-based analyses allowed us to predict functional consequences for rare, recurrent DDR mutations. We also developed a machine learning-based classifier that used gene expression data to identify alterations predicted to phenocopy known, deleterious TP53 mutations. The frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.