Three aspects of neuropsychological functioning in patients with ALS are examined. Contrary to previous research, a new psychometric study of psychological adjustment suggested significant depression-distress in this population and related psychological disturbance differentially to signs of upper versus lower motor neuron involvement and to respiratory failure. An association between ALS and impaired neuropsychological functioning is discussed through an examination of the clinical and pathologic literatures. ALS appears to be a multisystem degenerative disease with a variety of expressions that may frequently include loss of cognitive-behavioral competency with progressive involvement of the prefrontal cortex and, in a few instances, profound dementia. Finally, the article describes an analysis of trends in psychological adjustment and in the perception of physical capability over the course of a pilot clinical trial.