Amyotrophic lateral sclerosis (ALS) is an incurable degenerative motoneuronal disease. The complete suppression of motoneuronal death is the ultimate goal of ALS therapy. Two new prosurvival pathways have been recently demonstrated to antagonize neurotoxicity by familial ALS-linked mutant Cu/Zn-superoxide dismutase (FSOD1). Alsin, the product of the recently cloned ALS-causative gene, the ALS2 gene, is linked to a Rac1/phosphatidylinositol-3 kinase/Akt3 pathway that specifically suppresses motoneuronal death induced by FSOD1. Activity-dependent neurotrophic factor, originally identified as an anti-Alzheimer neurotrophic factor, has been shown to suppress motoneuronal death by FSOD1 through a prosurvival pathway mediated by Ca(2+)/calmodulin-dependent protein kinase IV. Activation of these novel anti-ALS pathways may serve as a promising way to suppress ALS-related motoneuronal cell death.