Although the cause of ALS remains unclear, approximately 10–20% of patients with ALS have a familial form of the disease. The evolution of molecular genetics technology has rapidly advanced our knowledge about the genetic causes of familial ALS, and then revealed that genetic factors play a role even in sporadic ALS. Uncovering the identity of the genetic factors in ALS has clarified the pathophysiology of the disease, such as disturbed RNA metabolism, impaired ubiquitin–proteasome system and autophagy degradation, cytoskeletal and axonal defect, and neuroinflammation. Based on the pathogenesis, new therapeutic strategies have been proposed and validated by using various approaches including antisense oligonucleotides, monoclonal antibodies, and cell therapies. On the contrary, the challenges to conduct more efficient clinical trials have been highlighted. We here present the possible pathogenesis, representative on–going clinical trials, and problems to overcome for therapies of ALS.