Modern human need for medicines is so extensive that it is thought to be a deep evolutionary behavior. There is abundant evidence from our Paleolithic and later prehistoric past, of survival after periodontal disease, traumas, and invasive medical treatments including trepanations and amputations, suggesting a detailed, applied knowledge of medicinal plant secondary compounds. Direct archeological evidence for use of plants in the Paleolithic is rare, but evidence is growing. An evolutionary context for early human use of medicinal plants is provided by the broad evidence for animal self-medication, in particular, of non-human primates. During the later Paleolithic, there is evidence for the use of poisonous and psychotropic plants, suggesting that Paleolithic humans built on and expanded their knowledge and use of plant secondary compounds.