Recurrent mutations in genes encoding key splicing factors, SF3B1, SRSF2, U2AF1, and ZRSR2 have been found in a variety of cancers, particularly in hematologic malignancies, including myelodysplastic syndromes, chronic myelomonocytic leukemia, acute myeloid leukemia, and chronic lymphocytic leukemia. Global mis-splicing of mRNAs targeted by aberrant splicing factors partly contributes to leukemogenesis through decrease protein expression of tumor suppressors and epigenetic modifiers, caused by mRNAs degradation of aberrantly spliced. Some of the mis-spliced mRNAs influence intracellular oncogenic pathways and cellular processes through a dysregulated expression of associated proteins, whereas others influence the function of co-mutated genes such as aberrant transcriptional regulators. Spliceosomal disruption is common in many cancers, making spliceosome an appealing therapeutic target. The findings that spliceosomal mutant cells rely on wild-type splicing machinery for survival and that splicing factor mutations occur in a mutually exclusive manner strongly suggest that inhibiting wild-type splicing machinery causes synthetic lethality in cancer cells with these mutations. We discuss the characteristics and oncogenic mechanisms of splicing factor mutations, as well as the development of novel treatment strategies targeting aberrant splicing factors in hematologic malignancies.