Autochthonous human cases of leishmaniasis in the United States are uncommon. We report three new cases of cutaneous leishmaniasis and details of a previously reported case, all outside the known endemic range in Texas. Surveys for enzootic rodent reservoirs and sand fly vectors were conducted around the residences of three of the case-patients during the summer of 2006; female Lutzomyia anthophora sand flies were collected at a north Texas and southeast Oklahoma residence of a case-patient, indicating proximity of a suitable vector. Urban sprawl, climatologic variability, or natural expansion of Leishmania mexicana are possible explanations for the apparent spread to the north and east. Enhanced awareness among healthcare providers in the south central region of the United States is important to ensure clinical suspicion of leishmaniasis, diagnosis, and appropriate patient management.