Therapeutic options for treating patients with metastatic colorectal cancer (CRC) have increased markedly over the past decade. Recent improvements in overall survival rates from 10 to 24 months have been achieved through the introduction of molecularly targeted agents to complement traditional cytotoxics, including agents directed against the EGF receptor (EGFR) pathway (cetuximab and panitumumab) and angiogenesis (bevacizumab, aflibercept and regorafenib). This progress has spurred intense efforts to develop further compounds that target key molecular pathways driving carcinogenesis. One major focus has been on the inhibition of oncogenic PI3K signaling, with diverse inhibitors currently in Phase I/II clinical trials. While achieving clear responses in some cancers, activity in CRC has been modest, with disease stabilization observed in approximately 10% of patients. Here, we discuss the potential opportunities of targeting the PI3K pathway in treating patients with metastatic CRC.