Amyotrophic lateral sclerosis (ALS) is a devastating and enigmatic disease with no cure. The single approved, available medication, Riluzole, only modestly slows disease progression. Nearly 30 potential medications, developed based on diverse hypotheses, have been extensively tried in the past 20 years, but this has been without success. On the other hand, incredible progress in animal models, molecular biology and neuroscience has led to the identification of a number of hereditary causes of familial ALS and generated many exciting hypotheses in ALS. Nevertheless, there is still a glaring deficit in our knowledge of the pathogenesis and cause of ALS. Consequently, if we are to understand and effectively treat this disease, we need to further investigate the disease mechanisms and cause in our ALS patients. We strongly believe that the key to this mystery is likely to exist in the patients themselves. However, studying patients with ALS poses many challenges because 1) ALS is relatively rare (1 to 2 cases per 100,000 population), 2) given its rapid progression, there is little time for research after diagnosis, 3) patients are generally diagnosed late in adulthood, leaving few immediate family members for study, and 4) access to the central nervous system tissue is highly limited. Despite these limitations and tremendous methodological challenges, ALS physicians and physician-scientists are still in the best position to study the cause and pathogenesis of ALS directly in patients. Further, we need not only to find creative and innovative ways to investigate this disease, but also, to work with basic scientists as close partners. Therefore, we propose to hold a conference to energize clinical or patient-oriented research in ALS. We specifically aim to: 1) bring ALS physicians, physician-scientists and basic scientists together to discuss a focused topic, clinical research (not clinical trials);2) review the current status of the pathogenesis and cause of ALS including clinical characteristics, biomarkers, epidemiology, and genetic and epigenetic studies, most of which are amenable to clinical research;3) encourage physicians to collaborate with basic scientists in order to consider the feasibility of developing clinical research with the aim of discovering the cause(s) and pathogenesis of ALS. Further, we will discuss methodological and funding issues that must be overcome in order to move clinical research forward;and 4) publish the results and recommendations from the conference as a supplement or as a white paper in a major neurology journal. The meeting will be designed to allow for the open exchange of ideas, and will hopefully work out strategies for developing very active clinical research in the future. It is imperative that physicians and scientists realize that, more than ever before, there is a serious need for such collaboration in ALS. We strongly believe that this meeting will be a step forward to finding the pathogenesis and cause(s), and eventually, the cure for this dreaded disease, ALS. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is one of the most devastating neurological diseases with no cure. Its pathogenesis and cause are not yet established. We propose an NIH ALS Conference in which physicians and basic scientists, who both specialize in ALS, will come together and discuss how to facilitate and energize clinical research to find the pathogenesis and cause of ALS in the future. This will be an important step to lead to the cure for ALS.