INTRODUCTIONAmyotrophic lateral sclerosis (ALS), also referred to as Lou Gehrig's disease, is characterized by the progressive loss of cells in the brain and spinal cord that leads to debilitation and death in 3 - 5 years. Only one therapeutic drug, riluzole, has been approved for ALS and this drug improves survival by 2 - 3 months. The need for new therapeutics that can postpone or slow the progression of the motor deficits and prolong survival is still a strong unmet medical need.AREAS COVEREDAlthough there are a number of drugs currently in clinical trials for ALS, this review provides an overview of the most promising biological targets and preclinical strategies that are currently being developed and deployed. The list of targets for ALS was compiled from a variety of websites including individual companies that have ALS programs and include those from the author's experience.EXPERT OPINIONProgress is being made in the identification of possible new therapeutics for ALS with recent efforts in understanding the genetic causes of the disease, susceptibility factors and the development of additional preclinical animal models. However, many challenges remain in the identification of new ALS therapeutics including: the use of relevant biomarkers, the need for an earlier diagnosis of the disease and additional animal models. Multiple strategies need to be tested in the clinic in order to determine what will be effective in patients.