A number of recent papers on the WWP2 E3 ubiquitin ligase and two novel WWP2 isoforms have revealed important biological insight and disease-specific functions, and also impacted on our understanding of ubiquitin ligases in cell cycle regulation, apoptosis and differentiation. Gene knockout studies suggest a developmental role for WWP2 in chondrogenesis via mechanisms involving cartilage-specific transcription factors. Furthermore, WWP2 isoforms have been shown to selectively target oncogenic signaling pathways linked to both the pTEN tumour suppressor and the TGFβ/Smad signaling pathway. Here, it is suggested that WWP2 isoforms have now emerged as central physiological regulators as well as promising new disease targets, and that the challenge ahead is to now develop highly selective WWP2 inhibitors with utility in cartilage disease such as osteoarthritis and as new anticancer strategies.