This commentary on the review by DA Saint in the current issue of the British Journal of Pharmacology focuses on the pathological role of late I(Na) in the heart, the evidence supporting inhibition of late I(Na) as a therapeutic target in ischaemic heart disease, and the therapeutic applications and challenges for development of new late I(Na) inhibitors. Recent reports from a large clinical outcome trial (MERLIN) of ranolazine, a drug known to inhibit late I(Na), indicated that it was safe and reduced recurrent ischaemia and arrhythmic activity. In combination with other results indicating that inhibition of late I(Na) reduces ischaemia, myocardial Ca(2+) overload, and electrical and mechanical dysfunction when late I(Na) is increased, the new clinical trial results suggest that reduction of cardiac late I(Na) is safe and therapeutically beneficial.