Neuropsychological research in patients with affective disorders shows heterogeneous results with regard to the severity and profile of cognitive impairments. In this paper we hypothesize that the investigation of clinical (subtypes, comorbidity, traumatization, personality, severity, diurnal swings, course, duration, age of onset, biased processing, rumination, motivation, experience of failure, sleep, suicidal tendencies, computer attitudes), demographic (age, education, gender) and neurobiological factors (structural and functional brain changes, glucocorticoids, medication, ECT) that are related to cognitive performance has specified the understanding of severity and profile of neuropsychological impairments. We reviewed the literature pertaining to clinical, demographic and neurobiological factors following Pubmed and PsychInfo databases using different combinations of general key-terms including "Affective Disorder," "Depression," "Mania," "Neuropsychological," "Neurobiological," "Moderator," and "Review" as well as more specific demographic, clinical and neurobiological search terms. Findings from the literature show that the consideration of these factors has improved knowledge about the severity of neuropsychological impairments in patients with affective disorders whereas the neuropsychological profile is still poorly understood. Despite limited understanding, however, the existent results provide promising suggestions for the development of treatment programs.