Purpose of Review <p>This review will summarize recent research into the diverse biological consequences of splicing factor mutations, and possible therapeutic vulnerabilities uncovered by such mutations, with a dedicated focus on chronic myelomonocytic leukemia.</p> Recent Findings <p>Splicing factor mutations dysregulate alternative splicing transcriptome-wide. The global nature of such dysregulation has pleiotropic effects on cellular function. Splicing factor mutations can alter NF-κβ and IFN-γ signaling, alter malignant hematopoietic cell differentiation, degrade the function of epigenetic complexes, and predispose cells to DNA replicative stress. Therapeutic strategies to target the altered biology of clones harboring splicing mutations have had varying degrees of success.</p> Summary <p>Because splicing factor mutations are highly prevalent in chronic myelomonocytic leukemia and many other hematologic malignancies, an understanding of their downstream effects and therapeutic vulnerabilities is of key interest in the field. This review highlights recent developments and opportunities for targeted therapies.</p>