Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disorder that is believed to have complex
genetic and environmental influences in the pathogenesis, but etiologies are unidentified for most patients. Until the
major causes are better defined, drug development is directed at downstream pathophysiological mechanisms, themselves
incompletely understood. For nearly 30 years, glutamate-induced excitotoxicity has lain at the core of theories behind the
spiraling events, including mitochondrial dysfunction, oxidative stress, and protein aggregation, that lead to neurodegenerative
cell death. One drug, riluzole, which possesses anti-glutamatergic properties, is approved as neuroprotective for
ALS. Following the achievement of the riluzole trials, numerous other agents with similar mechanisms have been tested
without success. This article provides an overview of excitotoxicity in ALS, focusing on the events that contribute to excess
glutamate, how the excess might damage nerve cells, and how this information is being harnessed in the development
of potential new neuroprotective agents. The work highlights clinical trials of drugs that have targeted the glutamate system,
comments on the potential role of glutamate as a biomarker and concludes with a section on future directions for the
field. As research uncovers elusive etiologies and brings clarity to pathophysiological mechanisms, the success of new
interventions will increasingly depend on the design of agents that target particular mechanisms for specific individuals.
The heady future of personalized drug regimens for ALS rests with medicinal chemists, the scientists whose ideas and
work produce these designer drugs.