Plaque disruption and thrombosis are determinants for the onset of acute ischemic syndromes. The presence of intracoronary thrombus is associated with an increased risk of complications during revascularization with balloon angioplasty. Thrombi avidly absorb light in the mid-infrared optical spectrum due to their high water content. The potential clinical advantages of the holmium laser as a source of thrombolysis include rapid removal of the target clot, vaporization of procoagulant reactants, elimination of a systemic lytic state, and facilitation of adjunct balloon angioplasty by concomitant plaque vaporization. Notably, while thrombolytic drug therapy treats only the acute cause, that is, thrombus, the laser has the potential for treating both thrombus and its underlying cause, that is, the atherosclerotic plaque. In vitro studies suggest that the effect of the holmium laser is achieved by nonselective, mechanical disruption of the irradiated thrombus, a mechanism unlike selective thrombolysis as induced by pulsed-dye lasers. Further basic and clinical research is needed to explore holmium laser-thrombus interactions and thus lead to optimal clinical application of this technology.