Parathyroid hormone-related protein (PTHrP), a polyprotein discovered in 1987, plays crucial roles not only in development and in various physiological events associated with normal life, but also in a number of pathological conditions such as cancer. PTHrP appears as the major causative agent in humoral hypercalcemia of malignancy (HHM) associated to a broad range of tumors. However, this is only one aspect of the multiple facets of PTHrP in cancer biology. Indeed, the complex growth factor-like properties of PTHrP has shed new light onto potential roles of this peptide in the regulation of tumor growth and invasion. Initial studies in breast, prostate and lung cancer and recent results in renal cell carcinoma (RCC) suggest such roles and highlight the therapeutic potential of PTHrP-targeting strategies in human cancer including RCC. In this review, the role of PTHrP in RCC tumorigenesis and its potential as a therapeutic target will be discussed.