ROR2 is a signaling receptor for Wnt ligands that is known to play important roles in limb development, but having no essential roles known in adult tissues. Recent evidence has implicated ROR2 in mediating both canonical and non-canonical signaling pathways. ROR2 was initially found to be highly expressed in osteosarcoma and renal cell carcinomas, and has recently been found in an increasingly long list of cancers currently including melanoma, colon cancer, melanoma, squamous cell carcinoma of the head and neck, and breast cancer. In the majority of these cancer types, ROR2 expression is associated with more aggressive disease states, consistent with a role mediating Wnt signaling regardless of the canonical or non-canonical signal. Because of the pattern of tissue distribution, the association with high-risk diseases, and the cell surface localization of this receptor, ROR2 has been identified as a potential high value target for therapeutic development. However, the recent discovery that ROR2 may function through non-kinase activities challenges this strategy and opens up opportunities to target this important molecule through alternative means.