Popeye domain-containing (POPDC) proteins are a novel class of cAMP-binding molecules that affect cancer cell behaviour and correlate with poor clinical outcomes. They are encoded by the POPDC genes POPDC1, POPDC2, and POPDC3. The deletion of POPDC genes and the suppression of POPDC proteins correlate with enhanced cancer cell proliferation, migration, invasion, metastasis, drug resistance, and poor patient survival in various human cancers. Overexpression of POPDC proteins inhibits cancer cell migration and invasion in vitro. POPDC proteins present promising anticancer therapeutic targets and here we review their roles in promoting cancer progression and highlight their potential as anticancer therapeutic targets.