Several therapies have shown promise in preclinical models of motor neuron disease. Several of these treatment approaches, however, failed in human studies. In moving forward with new promising therapies, it is important to first identify whether the past trials were unsuccessful due to wrong therapy and biological target or because of flaws in trial design and conduct. We review treatment development in ALS and discuss the strengths and limitations of past clinical trials. Better biomarkers of disease and markers of biological activity of the therapies under development are urgently needed. Obtaining information regarding dosage, pharmacokinetics, short-term safety and biological activity in well designed phase I and II studies is critical to the design of phase III trials that will yield meaningful results.