In the treatment of cancers and infectious diseases, several drugs are administered simultaneously. Riluzole is a only drug which prolongs survival in amyotrophic lateral sclerosis (ALS) patients, however its effect is modest. We review the preclinical data supporting combination treatment for ALS and discuss the possible combination treatment in patients with ALS. In vitro studies showed favorable results in combination of neurotrophic factors. The combination of BDNF and GDNF reduced motor neuron death after axotomy for more than either factor alone. CNTF and BDNF combination treatment in wobbler mice arrested paw deformity. In the treatment of ALS, riluzole is the only drug available by prescription. When combination treatment is considered in ALS, the most effective combination need to be addressed.