Metastatic colorectal cancer (mCRC) is the second most common cause of cancer-related death worldwide. In the mid-1980s, the median overall survival (OS) for patients with mCRC ranged from 10 to 12 months from the time of initial diagnosis. In more recent studies, this median has more than doubled and is commonly reported at more than 25 to 30 months. These improvements are due, in large part, to the introduction of multiple novel agents during the last 3 decades. Despite these improvements, however, nearly all patients treated with palliative chemotherapy will eventually develop resistance and ultimately succumb to progression of metastatic disease. Understanding the mechanisms by which malignant cells evade treatment could unlock novel therapeutic strategies that overcome resistance and improve survival. In this review, we will discuss some of the drivers of therapeutic resistance in patients with mCRC and present some novel strategies to overcome resistance.