Apoptosis-associated speck-like protein containing a CARD (ASC), also known as target of methylation-mediated silencing (TMS1) and PYD and CARD domain containing protein (PYCARD), is a 22 kD pro-apoptotic protein containing an N-terminal pyrin domain (PYD) and a C-terminal caspase recruitment domain (CARD). The TMS1 gene was originally found to be aberrantly methylated and silenced in various cancer cells. Expression of ASC can be induced by pro-apoptotic/inflammatory stimuli. In normal cells, this protein is localized to the cytoplasm; however, in cells undergoing apoptosis, it forms ball-like aggregates near the nuclear periphery. During apoptosis, ASC translocated from the cytosol to the mitochondria and associates with mitochondrial Bax to trigger cytochrome c release and subsequent apoptosis. The adaptor molecule ASC mediates AIM2-dependent caspase-1 activation. Recent studies also show that AIM2/ASC complex acts as a novel caspase-8 activation platform. Moreover, emerging reports show novel roles for ASC in disease conditions such as arthritis.