The sigma receptor, a broadly distributed integral membrane protein with a novel structure, is known to modulate various voltage-gated K⁺ and Ca²⁺ channels through a mechanism that involves neither G-proteins nor phosphorylation. The present study investigated the modulation of the heart voltage-gated Na⁺ channel (Na_v1.5) by sigma receptors. Sigma-1 receptor ligands (SKF10047 and (+)-pentazocine) and sigma-1/sigma-2 receptor ligands (haloperidol and ditolylguanidine) all reversibly inhibited Na_v1.5 channels to varying degrees in HEK293 cells and COS-7 cells, but the sigma-1 receptor ligands were less effective in COS-7 cells. The same four ligands also inhibited Na⁺ current in neonatal mouse cardiac myocytes. In sigma-1 receptor knock-out myocytes, the sigma-1 receptor specific ligands were far less effective in modulating Na⁺ current, but the sigma-1/sigma-2 receptor ligands modulated Na⁺ channels as well as in wild type. Photolabeling with the sigma-1 receptor photoprobe [¹²⁵I]-iodoazidococaine demonstrated that sigma-1 receptors were abundant in heart and HEK293 cells, but scarce in COS-7 cells. This difference was consistent with the greater efficacy of sigma-1 receptor specific ligands in HEK293 cells than in COS-7 cells. Sigma receptors modulated Na⁺ channels despite the omission of GTP and ATP from the patch pipette solution. Sigma receptor inhibition of Na⁺ current had no voltage dependence, and produced no change in channel kinetics. Na⁺ channels represent a new addition to the large number of voltage-gated ion channels inhibited by sigma receptors. The modulation of Na_v1.5 channels by sigma receptors in the heart suggests an important pathway by which drugs can alter cardiac excitability and rhythmicity.