Kirsten Rat Sarcoma (KRAS) gene somatic point mutations is one of the most prominently mutated proto-oncogenes known to date, and accounts for approximately 60% of all colorectal cancer cases. One of the most exciting drug development areas against colorectal cancer is the targeting of undruggable kinases and kinase-substrate molecules, although whether and how they can be integrated with other therapies remains a question. Current clinical trial data have provided supporting evidence on the use of combination treatment involving MEK inhibitors and either one of the PI3K inhibitors for patients with metastatic colorectal cancer to avoid the development of resistance and provide effective therapeutic outcome rather than using a single agent alone. Many clinical trials are also ongoing to evaluate different combinations of these pathway inhibitors in combination with immunotherapy for patients with colorectal cancer whose current palliative treatment options are limited. Nevertheless, continued assessment of these targeted cancer therapies will eventually allow patients with colorectal cancer to be treated using a personalized medicine approach. In this review, the most recent scientific approaches and clinical trials targeting KRAS mutations directly or indirectly for the management of colorectal cancer are discussed.