SPDEF, as a member of the ETS transcription factor family, was found to play important roles not only in some normal organs but also in some cancers. Scientists found that the significant increase of SPDEF in some cancers promotes tumor development, while some others found that the expression of SPDEF is lost in some cancers, and the loss of SPDEF is related to the proliferation, invasion, and metastasis. In this review, we summarized the function of SPDEF in normal tissues and its dual behaviors in different cancers, which may become a novel target in the diagnosis and therapy of cancers in the future. Besides, the multi-upstream regulatory mechanism of SPDEF plays different regulatory roles in different tumors, deserving further study. Moreover, there is one research, reporting that SPDEF plays a role in promoting mucus production during viral infection, and this may provide new ideas for future research about virus-associated cancer.