The gene encoding the splicing factor SF2/ASF is a proto-oncogene. The study found that SF2/ASF is upregulated in various human tumors, often due to amplification of its gene (*SFRS1*). Overexpression of SF2/ASF is sufficient to transform immortal rodent fibroblasts, which form sarcomas in nude mice. SF2/ASF controls the alternative splicing of several tumor suppressor and oncogene isoforms, such as BIN1, MNK2, and S6K1. Overexpression of SF2/ASF in cells leads to the inactivation of BIN1 and the generation of oncogenic isoforms of S6K1 and MNK2. SF2/ASF also promotes eIF4E phosphorylation by modulating the splicing of MNK2. Knockdown of SF2/ASF or its oncogenic isoform in transformed cells reverses the transformed phenotype and inhibits tumor growth in nude mice. These findings suggest that SF2/ASF is a powerful proto-oncogene and a potential target for cancer therapy.The gene encoding the splicing factor SF2/ASF is a proto-oncogene. The study found that SF2/ASF is upregulated in various human tumors, often due to amplification of its gene (*SFRS1*). Overexpression of SF2/ASF is sufficient to transform immortal rodent fibroblasts, which form sarcomas in nude mice. SF2/ASF controls the alternative splicing of several tumor suppressor and oncogene isoforms, such as BIN1, MNK2, and S6K1. Overexpression of SF2/ASF in cells leads to the inactivation of BIN1 and the generation of oncogenic isoforms of S6K1 and MNK2. SF2/ASF also promotes eIF4E phosphorylation by modulating the splicing of MNK2. Knockdown of SF2/ASF or its oncogenic isoform in transformed cells reverses the transformed phenotype and inhibits tumor growth in nude mice. These findings suggest that SF2/ASF is a powerful proto-oncogene and a potential target for cancer therapy.