Clinical trials in amyotrophic lateral sclerosis (ALS) have been conducted for over half a century now and have incorporated a wide variety of drugs. Most of these trials have had negative results and a cure remains elusive. The explosion in our understanding of molecular biology and parallel developments in clinical epidemiology have opened up a vast number of novel therapeutic strategies. However, advances in statistical analysis, computing, and global communications have also put greater pressure on scientific investigators to improve the design and implementation of clinical trials so that they permit rigorous testing of hypotheses within a solid ethical framework. This article documents the first published trial for all drugs tried clinically in the treatment of ALS, focusing in more detail on the large, multicenter trials of recent years, namely those involving riluzole, ciliary neurotrophic factor, insulin-like growth factor-I, brain-derived neurotrophic factor, and SR57746A. The problems in the design of trials in ALS are discussed, including the selection of end points and surrogate markers of disease progression, and the major parameters in ALS assessment are reviewed.