The nuclear factor-kappaB (NF-kappaB) and c-Jun NH2-terminal kinase (JNK) signaling pathways regulate diverse biological processes, including the immune and inflammatory response, cell growth, apoptosis, and tumour formation. Not surprisingly therefore defects to either pathway contributes to the progression of numerous human disorders. Enhancing our understanding of the mechanisms that control signaling through these pathways is therefore significant as it may enable development of specific treatments. In this regard, CYLD was recently identified as a negative regulator of NF-kappaB and JNK signaling. CYLD has a C-terminal catalytic domain characteristic of deubiquitinating enzymes, and this is essential for CYLD to remove ubiquitin from certain proteins that positively mediate signaling through the NF-kappaB and JNK pathways. Recent studies have revealed a requirement for CYLD in many different processes and have provided some insight into the underlying mechanisms.