The L-type Ca2+ channel plays a critical role in cardiac excitation and contraction and it is the main route for calcium influx into cardiac myocytes. The function of the channel can be modified during alterations in cellular redox state. A reduced cellular state such as during acute hypoxia can alter the basal channel activity and the sensitivity of the channel to beta-adrenergic receptor stimulation. In cardiac myocytes thiol reducing agents mimic the effect of hypoxia suggesting an involvement of cysteines on the channel protein or a regulatory protein. We have experimental evidence this can lead to altered cellular excitation, induction of early afterdepolarizations and arrhythmia. Conversely we have found that an increase in cellular oxidative stress can increase channel activity and persistently alter cellular calcium homeostasis. The response leads to an increase in cellular protein synthesis consistent with the development of hypertrophy. We have demonstrated that direct glutathionylation of the channel protein occurs during oxidative stress including during ischemia reperfusion injury and in the failing human heart. Using site directed mutagenesis we have now identified the reactive cysteines responsible for altered channel function during changes in cellular redox state. The proposed role of the cysteines in the regulation of channel activation and inactivation will be discussed.