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SOS1 is a crucial guanine nucleotide exchange factor (GEF) that plays a key role in the activation of eukaryotic RAS GTPases, serving as a critical node in the highly conserved RAS/MAPK signaling pathway. Dysregulation of the RAS-MAPK pathway, which is frequently driven by oncogenic RAS mutations, is implicated in approximately 30% of all human cancers, making it one of the most prevalent oncogenic drivers. As a direct activator positioned upstream of RAS, and in view of the quick appearance of resistance to a wide variety of recently developed allele-specific KRAS inhibitors, SOS1 constitutes a highly promising therapeutic target for a wide spectrum of RAS-driven malignancies, offering a strategy to inhibit oncogenic signaling independently of specific RAS mutations and to potentially help overcome resistance mechanisms associated with direct RAS inhibitors. Over the past three decades, a substantial body of preclinical evidence has accumulated regarding the potential of SOS1 as a therapeutic target. Focusing preferentially on data generated using patient-derived experimental contexts, we will provide in this review a comprehensive evaluation of a variety of recently developed small-molecule SOS1 inhibitory drugs and SOS1 degraders. Specifically, we describe here their specific therapeutic responses elicited in a variety of preclinical, in vitro and in vivo models involving different specific tumor types and cell lines harboring different oncogenic driver mutations. Furthermore, we highlight promising synergistic outcomes of the SOS1 inhibitors in combination with other RAS/MAPK pathway antagonists and discuss cases where SOS1 inhibition was reported to prevent or overcome resistance to current, FDA-approved RAS inhibitors. We also outline the clinical trials currently underway evaluating SOS1 inhibitors. Additionally, we explore the relatively underestimated potential of SOS2 as a therapeutic target, alongside the current state of development for SOS2 inhibitors. Finally, we address several underexplored clinical avenues regarding SOS1 inhibition for the treatment of specific cancer subtypes.