The application of next-generation sequencing technologies to interrogate the genome of human hematologic malignancies is providing promising insights into their molecular etiology and into the pathogenesis of seemingly unrelated malignancies. Among the somatic mutations identified by this approach are ones that target components of the spliceosome, a ribonucleoprotein complex responsible for the posttranscriptional processing of primary transcripts to form mature messenger RNA species. These mutations were initially detected in patients with chronic lymphocytic leukemia or a myelodysplastic syndrome, but can also occur at relatively high frequency in some solid tumors, including uveal malignant melanoma, adenocarcinoma of the lung, and estrogen receptor-positive breast cancers. Their presence in a variety of malignancies suggests that the spliceosomal mutations may play a fundamental role in defining the malignant phenotype. The development and testing of drugs that eliminate cells bearing a spliceosomal mutation, or normalize their altered transcript splicing patterns, are therefore a priority. Here, we summarize the effects of spliceosome-associated mutations on transcript processing in vitro and in vivo, and their impact on disease initiation and/or progression and patient outcome. Moreover, we discuss the therapeutic potential of compounds already known to target splicing factor 3B subunit 1 (SF3B1), an essential component of the spliceosome that is frequently mutated.