Phosphatase of Regenerating Liver-3 (PRL3) was discovered in 1998 and was subsequently found to be correlated with cancer progression and metastasis in 2001. Extensive research in the past two decades has produced significant findings on PRL3-mediated cancer signaling and functions, as well as its clinical relevance in diverse types of cancer. PRL3 has been established to play a role in many cancer-related functions, including but not limited to metastasis, proliferation, and angiogenesis. Importantly, the tumor-specific expression of PRL3 protein in multiple cancer types has made it an attractive therapeutic target. Much effort has been made in developing PRL3-targeted therapy with small chemical inhibitors against intracellular PRL3, and notably, the development of PRL3-zumab as a novel cancer immunotherapy against PRL3. In this review, we summarize the current understanding of the role of PRL3 in cancer-related cellular functions, its prognostic value, as well as perspectives on PRL3 as a target for unconventional immunotherapy in the clinic with PRL3-zumab.