The oncogenic impact of somatic driver alterations is shaped by tissue context. Classifying alterations by cancer type and evaluating their context-specific properties requires large cohorts of genomically profiled and clinically annotated tumors. Here, we define cancer type-specific patterns of driver alterations, including 164 newly-identified hotspots, in 54,331 tumors from 48,179 patients spanning 448 histological cancer subtypes. One-third of all drivers arose in non-canonical contexts and exhibited distinct features including increased subclonality, later emergence, and divergent biological properties. Within cancer types, gene fusions and other distinct patterns of co-occurring drivers are indicative of earlier age of disease onset. We also identify ancestry-specific differences in human leukocyte antigen (HLA)-restricted driver neoantigens affecting T-Cell receptor therapy eligibility, and demonstrate cancer-type specific patterns of intrinsic resistance via somatic HLA loss. Our findings highlight that functional roles of driver alterations depend on the cancer types and clinical contexts in which they arise.