A number of successful systemic therapies are available for the treatment of disseminated cancers. However, tumor response is often transient, and therapy frequently fails due to emergence of resistant populations. The latter reflects the temporal and spatial heterogeneity of the tumor microenvironment as well as the evolutionary capacity of cancer phenotypes to adapt to therapeutic perturbations. Resistance to either chemotherapy and targeted agents limits the effectiveness of current cancer therapies, including those used to treat metastatic colorectal cancer (mCRC) which is one of the leading causes of cancer-related death worldwide. Resistance to therapeutic drugs can be already present at diagnosis or it can develop after treatment. These two forms of resistance are respectively called intrinsic and acquired. The identification of mechanisms of drug resistance may highlight new biomarkers useful to predict the clinical outcome or the likely responsiveness to pharmacological treatment of those metastatic CRC patients who cannot benefit from current therapeutic regimen. Moreover, the recognition of panels of biomarkers may suggest new strategies to overcome resistance by rational drug design and combination treatment. In this review, we describe molecular mechanisms of resistance to chemotherapies and targeted agents that may be relevant to colorectal cancer and the possible strategies to overcome the resistance.