Colorectal cancer (CRC) arises by a continuous process of genetic diversification and clonal evolution. Multiple genes and pathways have a role in tumor initiation and progression. The gradual accumulation of genetic and epigenetic processes leads to the establishment of adenoma and cancer. The important 'driver' mutations in tumor suppressor genes (such as TP53, APC, and SMAD4) and oncogenes (such as KRAS, NRAS, MET, and PIK3CA) confer selective growth advantages and cause CRC advancement. Clonal evolution induced by therapeutic pressure, as well as intra-tumoral heterogeneity, has been a great challenge in the treatment of metastatic CRC. Tumors often develop resistance to treatments as a result of intra-tumor heterogeneity, clonal evolution, and selection. Hence, the development of a multidrug personalized approach should be prioritized to pave the way for therapeutics repurposing and combination therapy to arrest tumor progression. This review summarizes how selective drug pressure can impact tumor evolution, resulting in the formation of polyclonal resistance mechanisms, ultimately promoting cancer progression. Current strategies for targeting clonal evolution are described. By understanding sources and consequences of tumor heterogeneity, customized and effective treatment plans to combat drug resistance may be devised.