This review gives an up-to-date account of the current state of research on neuropsychiatric complications associated with efavirenz therapy and critiques the methods used in previous studies. The authors suggest an extension of current research strategies using psychophysiological concepts and including behavioral regulation models. From a practical perspective, these may contribute to better screening methods for the identification of those at risk for neuropsychiatric complications and the improvement of neuropsychiatric monitoring during efavirenz treatment. From a theoretical viewpoint, the suggested research paradigms may help to move beyond the current state of descriptive approaches and thus improve our limited understanding of underlying mechanisms.