Significant progress in understanding the cellular mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has not been matched with the development of therapeutic strategies to prevent disease progression. The multiple potential causes and relative rarity of the disease are two significant factors that make drug development and assessment in clinical trials extremely difficult. We review recent progress in promoting therapeutics into clinical trials and highlight the value of moderate throughput screening for the acceleration and improvement of drug design.