Our awareness of the range of signalling pathways which can be influenced by CO continues to grow, and in recent years ion channels have become recognised as a major family of effectors for many of the biological actions of this gasotransmitter (Peers, 2011;Wilkinson and Kemp, 2011). We have reported that CO inhibits L-type Ca2+ channels in cardiac myocytes in a splice variant-dependent manner via redox modulation of key cysteine residues in the C-terminal region of the channel protein. Redox modulation involved CO increasing the production of reactive oxygen species (ROS) from mitochondria (Scragg et al., 2008). We suggested at the time that this action may account for the known protective effects of heme oxygenase-1 (HO-1) expression, following myocardial ischemia (Peers and Steele, 2012). However, subsequent studies have revealed that CO can exert pro-arrhythmic effects, and this appears to occur via modulation of cardiac Na+ channels. Thus, following exposure to CO, the normally rapidly inactivating Na+ current is reduced in amplitude, but inactivation is dramatically slowed, giving rise to a sustained ‘late’ Na+ current. This effect appears to arise due to stimulation of NO formation, and subsequent S-nitrosylation of the channel protein (Nav1.5). As a consequence of this, we often observed early afterdepolarization-like arrhythmic events which can be prevented by ranolazine, an inhibitor of the late Na+ current. Clearly, the overall effect of CO in the myocardium depends on the net effect of its action at different ion channels, as well as other potential targets. Most recently we have identified T-type Ca2+ channels as a new site of action of CO. Inhibition of T-type channels by CO is only reversed by exposure to a reducing agent such as dithiothreitol, suggesting a ROS-mediated action. However, we have not been able to inhibit this effect of CO using a range of inhibitors of various intracellular sources of ROS. CO inhibition of T-type channels has implications in a number of physiological and pathological scenarios. Since T-type channels can strongly influence cell proliferation (Lory et al., 2006), we are investigating the effects of CO in proliferation of vascular smooth muscle and in cancer cells. Our preliminary studies suggest that proliferation can be slowed either by known blockers of T-type channels (e.g. mibefradil), induction of HO-1, or by application of CO donors such as CORM-3. Importantly, HO-1 induction or CO donors have no additional effect in the presence of mibefradil. These findings suggest that CO regulation of T-type channels may have clinically useful potential in the treatment of proliferative disorders and, given the numerous roles of T-type channels in the nervous system, there is further potential for exploiting this pathway.