The splicing factor SF2/ASF is a proto-oncogene involved in cancer. It is upregulated in various human tumors, partly due to gene amplification. Overexpression of SF2/ASF transforms immortal rodent fibroblasts into sarcomas in nude mice. SF2/ASF regulates alternative splicing of tumor suppressor genes such as BIN1, and kinases like MNK2 and S6K1. The resulting isoforms of these genes lack tumor-suppressor activity or promote oncogenic activity. Knockdown of SF2/ASF or its isoform-2 reduces transformation in vitro and in vivo. SF2/ASF is essential for cell viability and embryonic development, and its overexpression promotes cell proliferation and inhibits apoptosis. It also modulates the alternative splicing of several genes, including RPS6KB1, leading to the production of an oncogenic isoform of S6K1. SF2/ASF induces phosphorylation of eIF4E, which contributes to its oncogenic activity. Knockdown of SF2/ASF or its isoform-2 reverses transformation, indicating its role in tumor maintenance. These findings suggest that SF2/ASF is a potential target for cancer therapy.The splicing factor SF2/ASF is a proto-oncogene involved in cancer. It is upregulated in various human tumors, partly due to gene amplification. Overexpression of SF2/ASF transforms immortal rodent fibroblasts into sarcomas in nude mice. SF2/ASF regulates alternative splicing of tumor suppressor genes such as BIN1, and kinases like MNK2 and S6K1. The resulting isoforms of these genes lack tumor-suppressor activity or promote oncogenic activity. Knockdown of SF2/ASF or its isoform-2 reduces transformation in vitro and in vivo. SF2/ASF is essential for cell viability and embryonic development, and its overexpression promotes cell proliferation and inhibits apoptosis. It also modulates the alternative splicing of several genes, including RPS6KB1, leading to the production of an oncogenic isoform of S6K1. SF2/ASF induces phosphorylation of eIF4E, which contributes to its oncogenic activity. Knockdown of SF2/ASF or its isoform-2 reverses transformation, indicating its role in tumor maintenance. These findings suggest that SF2/ASF is a potential target for cancer therapy.