Purpose of Review <p>Amyotrophic lateral sclerosis (ALS) is a devastating, multifactorial disease with no effective long-term treatment, leading to a median survival time of less than five years after diagnosis. This review aims to critically evaluate emerging therapeutic strategies for ALS—with a special focus on combination and synergistic approaches that target multiple pathogenic mechanisms—with the goal of identifying strategies that may reduce biomarkers of damage, improve quality of life, and extend patient survival.</p> Recent Findings <p>To date, only two drugs (riluzole and edaravone) have been approved by the FDA, and their benefits are limited to mitigating certain aspects of the disease without significantly prolonging life expectancy. In recent years, considerable time, money, and effort have been invested in exploring various treatment options, including agents such as TUDCA, Nuedexta, tofersen, masitinib, and NurOwn. A notable trend has been the investigation of combined and synergistic therapies that employ two or more repositioned drugs, often alongside adjuvant cell or gene therapies, to target different mechanisms concurrently. Numerous clinical trials, many currently in phases II and III, are evaluating these approaches, though more in-depth research with larger patient cohorts remains necessary.</p> Summary <p>This review discusses emerging pathophysiological targets and presents an in-depth analysis of both approved therapies and those nearing clinical approval for ALS. By critically examining the current landscape of clinical trials focused on combination strategies, we highlight both the promise and the challenges of these multi-target interventions. Ultimately, the goal is to provide a clearer path forward in the development of effective treatments that can substantially alter the course of ALS.</p>