The treatment of metastatic colorectal cancer (mCRC) remains one of the largest hurdles in cancer therapeutics to date. The most advanced treatment option for mCRC patients are anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) that bind to and inhibit the activity of EGFR. While the use of anti-EGFR mABs has had great impact in the treatment of mCRC, it has now been widely accepted that mCRC tumors with a mutation in the small GTPase KRAS do not respond to these therapies. KRAS mutations allow for EGFR independent activation of various oncogenic signaling cascades. In attempts to inhibit KRAS mutant tumor growth, BRAF, MEK and farsenyltransferase inhibitors have been used, however, their clinical efficacy is still accruing in the setting of CRC. Recent data suggests that various other inhibitors, including inhibitors of Src family kinases (SFK) and hepatocyte growth factor receptor (MET), may have potential preclinical and clinical success in KRAS mutant tumors. Additionally, it is becoming increasingly clear that different KRAS missense mutations may have varied biological responses to cetuximab, suggesting that cetuximab may still be a potential therapeutic option in some KRAS mutant tumors. In this review, we highlight the importance for both improved multimodality approaches for treating KRAS mutant mCRC tumors and stratification of KRAS mutations in response to different treatment regimes in order to optimize the best possible care for mCRC patients.