ALS is a fatal untreatable disease involving degeneration of motor neurons. Μultiple causative genes encoding proteins with versatile functions have been identified indicating that diverse biological pathways lead to ALS. Gene and stem cell-based therapies are not expected to enter clinical practice anytime soon. Thus, chemical entities represent a promising choice to delay ALS progression, attenuate symptoms and/or increase life expectancy. Various compounds proved effective in transgenic models overexpressing distinct ALS causative genes but showed no efficacy in clinical trials. Notably, while animal models provide a uniform genetic background for preclinical testing, ALS patients are not stratified, and the distinct genetic forms of ALS are treated as a unique group which could explain the discrepancy between treating genetically homogeneous mice and quite heterogeneous patient cohorts. We suggest that chemical entity-genotype correlation should be exploited to guide patient stratification for therapy.