Over the past several decades, many attempts have been made to trace the route of the Hernando de Soto expedition through Texas. All of these efforts have been based on an incomplete understanding of the archeological record relating to the 16th century in Texas. A number of archeological investigations have been conducted over the past several decades, and provide better knowledge of the late prehistoric period in Texas. This article examines the route of the de Soto expedition, under the command of Luis de Moscoso, through the state based on our present archeological knowledge. The expedition is proposed to have entered Texas along the Red River and traveled southward until reaching Caddoan settlements near Nacogdoches in the east-central portion of the state. From here the expedition traveled westward until reaching the Guadalupe River of south-central Texas, where the soldiers abandoned hopes of reaching New Spain by an overland route. Implications of the proposed route upon Native American populations of eastern Texas are discussed and related to the possible introduction of European diseases.