Which ion channel is the most important for regulating vascular tone? Which one is responsible for controlling the resting membrane potential or repolarization? Which channels are recruited by different intracellular signalling pathways or change in certain vascular diseases? Many different ion channels have been identified in the vasculature over the years and claimed as future therapeutic targets. Unfortunately, several of these ion channels are not just found in the vasculature, with many of them also found to have prominent functional roles in different organs of the body, which then leads to off-target effects. As cardiovascular diseases are expected to increase worldwide to epidemic proportions, ion channel research and the hunt for the next major therapeutic target to treat different vascular diseases has never been more important. However, I believe that the question we should now be asking is: which ancillary subunits are involved in regulating specific ion channels in the vasculature and do they have the potential to be new therapeutic targets?