Neurotrophic factors have a large range of activities in the nervous system that consist of functions in development, plasticity, neurogenesis, disease, and injury. In the context of amyotrophic lateral sclerosis (ALS), it has long been hypothesized that lack of neurotrophic growth factors is one of the neuro toxic contributors to thedisease that results in death of motor neurons. This has led to a considerable number of clinical trials undertaken involving neurotrophic therapy for ALS, although none have shown benefit. This chapter will review the cause and pathology of ALS and how neurotrophic factors relate to neurotoxicity in this disease. The treatments targeted at neurotoxicity and results of trials will be discussed, in particular neurotrophic factors. This will include glial cell-derived neurotrophic factor (GDNF), brain-derived growth factor (BDNF), neurotrophin-3 (NT-3), ciliary neurotrophic factor (CNTF), insulin-like growth factor (IGF), vascular endothelial cell growth factor (VEGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF). Also highlighted is the potential for reexamining neurotrophic factors as treatments for ALS, including new delivery methods.