Colorectal cancer treatment has undergone a paradigm shift. We no longer see this disease as a singular, anatomic tumor type but rather a set of disease subgroups. Largely because of a better understanding of cancer biology and the introduction and integration of molecular biomarkers-the premise of precision therapy-we are beginning to direct treatments toward the right tumor target(s) in the right patients. The field of molecular profiling is continually evolving, and new biomarkers are constantly being discovered that have investigational, therapeutic, and/or prognostic implications-negative or positive. To date, only a few biomarkers have sufficient actionable, clinical implication to earn international guideline-recommended routine testing. Hence, it is vital that the treating oncologist should know which biomarkers to assess, when in the treatment course to test for them, and how the test is to be done. Correct interpretation of profiling results is imperative. Herein, we focus on international guideline-recommended mutation testing for patients prior to their colorectal cancer treatment initiation. The clinical applications of circulating tumor DNA (ctDNA) in patients with metastatic disease, based on our current knowledge and capabilities, are also addressed.