Abstract Amyotrophic Lateral Sclerosis (ALS) is a slowly progressing neurodegenerative disease that affects motor neurons of the nervous system. Despite the identification of many potential therapeutics targeting pathogenic mechanisms in in vitro models, there has been limited progress in translating them into a successful pharmacotherapy in the animal model of ALS. Further, efforts to translate any promising results from preclinical trials to effective pharmacotherapies for patients have been unsuccessful, with the exception of riluzole, the only FDA-approved medication, which only modestly extends survival both in the animal model and in patients. Thus, it is essential to reconsider the strategies for developing ALS pharmacotherapies. Growing evidence suggests that problems identifying highly effective ALS treatments may result from an underestimated issue of drug bioavailability and disease-driven pharmacoresistance, mediated by the ATP-binding cassette (ABC) drug efflux transporters. ABC transporters are predominately localized to the lumen of endothelial cells of the blood–brain and blood–spinal cord barriers (BBB, BSCB) where they limit the entry into the central nervous system (CNS) of a wide range of neurotoxicants and xenobiotics, but also therapeutics. In ALS, expression and function of ABC transporters is increased at the BBB/BSCB and their expression has been detected on neurons and glia in the CNS parenchyma, which may further reduce therapeutic action in target cells. Understanding and accounting for the contribution of these transporters to ALS pharmacoresistance could both improve the modest effects of riluzole and set in motion a re-evaluation of previous ALS drug disappointments. In addition, identifying pathogenic mechanisms regulating ABC transporter expression and function in ALS may lead to the development of new therapeutic strategies. It is likely that novel pharmacological approaches require counteracting pharmacoresistance to improve therapeutic efficacy. This article is part of a Special Issue entitled ALS complex pathogenesis.