Highly recurrent somatic mutations in the gene encoding the core splicing factor SF3B1 are drivers of multiple cancer types. SF3B1 is a scaffold protein that orchestrates multivalent protein–protein interactions within the spliceosome that are essential for recognizing the branchsite (BS) and selecting the 3′ splice site during the earliest stage of pre-mRNA splicing. In this review, we first describe the molecular mechanism by which multiple oncogenicSF3B1mutations disrupt splicing. This involves perturbation of an early spliceosomal trimeric protein complex necessary for accurate BS recognition in a subset of introns, which leads to activation of upstream branchpoints and selection of cryptic 3′ splice sites. We next discuss how specific transcripts affected by aberrant splicing inSF3B1-mutant cells contribute to the initiation and progression of cancer. Finally, we highlight the prognostic value and disease phenotypes of different cancer-associatedSF3B1mutations, which is critical for developing new targeted therapeutics againstSF3B1-mutant cancers still lacking in the clinic.