<p>Neoadjuvant therapy plays an increasingly important role in the multidisciplinary management of gastrointestinal cancers. While multimodal strategies are well established in rectal cancer, the role of neoadjuvant therapy in colon cancer remains under investigation. Recent advancements in molecular profiling and systemic therapies have underscored the biological heterogeneity of colorectal tumors, leading to more personalized approaches in the palliative setting but also in neoadjuvant strategies. This review explores the evolving role of neoadjuvant systemic treatment strategies in microsatellite stable (MSS) and high microsatellite instability (MSI-h) colorectal cancer, examining key clinical trials and future directions aimed at optimizing personalized treatment approaches for localized colorectal cancer.</p>