Synchronous colorectal cancer is a rare subtype of colorectal carcinoma defined by the presence of 2 or more primary tumors simultaneously or within 6 months of initial detection. The overall impact of a synchronous presentation on prognosis is not yet clear. Surgical resection is the primary treatment. However, higher rates of local recurrence and metastasis in synchronous colorectal cancer demand greater exploration of the role of adjuvant therapy. The increased frequency of microsatellite instability observed in synchronous colorectal cancer also affects therapy selection. Similarly, activating PIK3CA mutations are regularly noted in colorectal cancer, but their role in a synchronous presentation has not yet been described. We report a case of a young patient with a synchronous recto-sigmoid colorectal carcinoma complicated by microsatellite instability and an activating PIK3CA mutation-a presentation as of yet unreported in literature. We also review the impact of these molecular events on the efficacy of several chemotherapies and targeted therapies.