Epithelial splicing regulatory protein 1 (ESRP1) and 2 (ESRP2) are members of the hnRNP family of RNA binding proteins that regulate alternative splicing events associated with epithelial phenotypes. These proteins play crucial roles during organogenesis, including craniofacial and epidermal development as well as branching morphogenesis in the lungs and salivary glands. Recent reports have also addressed their roles during cancer progression. Expression of ESRP proteins is low in normal epithelium but upregulated in carcinoma in situ and advanced carcinomas. Intriguingly, they are downregulated in invasive fronts. The plastic nature of ESRP expression suggests dual roles for them in cancer progression. Consistently, it has been shown that ESRPs suppress motility and anchorage-independent growth of cancer cells while supporting cell survival by enhancing resistance to reactive oxygen species. Regulatory circuits that fine-tune ESRP gene expression have recently emerged. Here, we summarize recent findings on the molecular mechanisms by which ESRPs exert positive as well as negative effects on cancer progression.