Thousands of somatic mutations accrue in most human cancers, and their causes are largely unknown. We recently showed that the DNA cytidine deaminase APOBEC3B accounts for up to half of the mutational load in breast carcinomas expressing this enzyme. Here we address whether APOBEC3B is broadly responsible for mutagenesis in multiple tumor types. We analyzed gene expression data and mutation patterns, distributions and loads for 19 different cancer types, with over 4,800 exomes and 1,000,000 somatic mutations. Notably, APOBEC3B is upregulated, and its preferred target sequence is frequently mutated and clustered in at least six distinct cancers: bladder, cervix, lung (adenocarcinoma and squamous cell carcinoma), head and neck, and breast. Interpreting these findings in the light of previous genetic, cellular and biochemical studies, the most parsimonious conclusion from these global analyses is that APOBEC3B-catalyzed genomic uracil lesions are responsible for a large proportion of both dispersed and clustered mutations in multiple distinct cancers.