SET (SE translocation, SET) is an evolutionarily conserved gene broadly expressed in various human tissues, especially in the gonadal and neural system. As a multitasking protein, SET is involved in essential cell processes such as histone modification, chromatin remodeling, DNA repair, gene transcription, and androgen synthesis. Recent studies showed that SET is overexpressed in breast cancers, ovary cancers and a variety of other malignancies. The strong correlation between SET expression levels and survival of ovarian cancer patients, and SET-mediated activation of androgen synthesis, strongly indicated that this factor may play a significant role in gynecologic cancers. Here, we summarized data pertaining to the pathological implications of SET in tumorigenesis and cancer progression. We analyzed how SET, through the PP2A-dependent and PP2A-independent pathways, may regulate different cell functions. Potential interactions among these pathways and future studies on SET’s oncogenic activities are also discussed.