AbstractThe increasing complexity of the pathways implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS) has stimulated intensive research in many directions. Genetic analysis of familial ALS has yielded six loci and one disease gene (SOD1), initially suggesting a role for free radicals in the disease process, although the mechanisms through which the mutant exerts toxicity and results in selective motor neuron death remain uncertain. Numerous studies have focused on structural elements of the affected cell, emphasizing the role of neurofilaments and peripherin and their functional disruption in disease. Other topics examined include cellular homeostasis of copper and calcium, particularly in the context of oxidative stress and the processes of protein aggregation, glutamate excitotoxicity, and apoptosis. It has become evident that there is considerable interplay between these mechanisms and, as the role of each is established, a common picture may emerge, enabling the development of more targeted therapies. This study discusses the main areas of investigation and reviews the findings. © 2002 John Wiley & Sons, Inc. Muscle Nerve 25: 135–159, 2002 DOI 10.1002/mus.10000