Chronic consumption of several drugs of abuse (cannabis, stimulants, opioids) has been associated with the presence of neuropsychological impairments in a broad range of functions. Nevertheless, in recent years neuropsychological research on substance abuse has focused on the study of impairments in the executive functions linked to the prefrontal cortex and their influence on the personality, cognitions, and behaviors of the substance abusers. The aim of our review is, first, to summarize the main neuropsychological impairments shown by classic studies, as well as these new discoveries in executive functioning; second, to consider the mediating role of neuropsychological status on treatment outcomes and analyze the impact of these impairments in clinical practice with drug addicts; and third, to review the principal methodological challenges associated with research in the field of the neuropsychology of substance abuse. We also highlight the convenience of intervening in those functions most relevant to the abusers' persistence in consumption and risk of relapse.