Despite recent successes, metastatic colorectal cancer remains a difficult cancer to treat. Since the initial discovery that PI-3-Kinase/AKT signaling played an important part in the growth and survival of colorectal tumors, preclinical studies have suggested that inhibitors of this pathway may have a role to play as potential therapeutics. With the surge of inhibitors of PI-3-Kinase from both academia and pharmaceutical companies rapidly moving through early clinical trials, the question of whether these preclinical studies will translate to patients will soon be answered. However, the failure or success of these agents will depend on correctly identifying patients that may benefit, as has been seen with EGFR inhibitors recently approved for treating this disease. Determining the potential of PI-3-Kinase inhibitors in colorectal cancer will depend on factors such as correctly monitoring biomarkers and patient response, enriching clinical trials by proactively stratifying patients into populations based on markers shown to not only predict response to these inhibitors, but also markers which may predict for lack of response, and determining how to combine these inhibitors with both current cytotoxic therapies and approved and emerging targeted therapies with optimal benefit. How these goals may be achieved in the current oncology landscape is addressed in this review with an emphasis on how these agents fit the goal of achieving personalized medicine.