Endovenous laser treatment (ELT) has evolved into a frequently employed modality for the treatment of leg varicose veins. Due to the very high complete response rates, minimal complications and side effects, and the possibility to monitor therapeutic outcome noninvasively by duplex ultrasound, a considerable amount of reports have been published on clinical and translational studies, whereas disproportionally few studies have been performed to elucidate the molecular and cellular basis for post-ELT vessel obliteration. Consequently, this review addresses the putative molecular and cellular mechanisms responsible for varicose vein obliteration following laser irradiation in the context of endovenous laser–tissue interactions. First, the histological profile of laser-treated varicose veins is summarized, and an account is given of the temporal and spatial dynamics of cells involved in inflammation and remodeling in the heat-affected vein segment. Inasmuch as thrombotic occlusion of the venous lumen blocks circulatory access to the affected vessel segment and thermal damage in the vascular wall causes most cells to die, the majority of cells involved in inflammation and remodeling have to be recruited. Second, the (possible) biochemical triggers for the chemotactic attraction of immune cells and fibroblasts are identified, comprising (1) thermal coagula, (2) thrombi, (3) dead and dying cells in the vein wall, and (4) thermally denatured extracellular matrix proteins in the vein wall. The molecular biology underlying the chemotactic signaling and subsequent obliterative remodeling is elucidated. Finally, the relative contribution of every biochemical trigger to obliterative remodeling is addressed.