In this study some particular and puzzling aspects of amyotrophic lateral sclerosis (ALS) are discussed, with an emphasis on the role of neocortical evolution. Other issues explored include the nature of the clinical deficit in ALS; anatomical and evolutionary aspects of the neocortex, motor cortex, and corpus callosum; and some discussion as to when ALS begins. In common with other neurodegenerative diseases, ALS may result from dysfunctional neocortical circuitry. It is suggested that the disease starts some years prior to clinical onset, possibly in adolescence, or even earlier, when there is marked alteration of anatomy, physiology, and biochemistry of the neocortex. The failure of naturally occurring animal models of ALS or models that truly replicate the human disease may reflect the unique, continued, and increased neocortical evolution of modern humans. Muscle Nerve 40: 297-304, 2009.