Colorectal cancer (CRC) is a heterogeneous disease, and the search for clinical and molecular prognostic and predictive factors is thus necessary to better tailor each individual patient's management. Primary tumor location (PTL) seems to act as a master prognostic factor pooling different clinical, pathological, and molecular poor prognostic factors. In fact, right-sided (RS) CRC patients are more frequently female and elderly with microsatellite unstable, BRAF mutated, CpG island methylator phenotype (CIMP)-high, poorly differentiated tumors, compared to left-sided (LS) CRC patients. PTL does not seem to clearly influence disease-free survival (DFS) in localised colon cancer even though the opposite prognostic value of RS tumors on DFS depending on RAS/BRAF mutational status has been recently suggested in these patients. In metastatic CRC (mCRC), the poor prognosis associated with RS tumors is confirmed in the most recent publications in the era of double and triple chemotherapeutic regimens and targeted agents. Concerning the predictive value of PTL, in patients with RAS wild-type mCRC in the first-line setting, anti-epidermal growth factor receptor (EGFR) therapy combined with chemotherapy appears to be more effective than bevacizumab in LS CRC, while patients with RS CRC benefit less from anti-EGFR therapy, and intensive chemotherapy plus bevacizumab may be more appropriate but EGFR antibodies remain an option if objective response is needed. Due to the limitation of the current data (unplanned and retrospective analyses), these conclusions must be interpreted with caution. Clinical trials in RS CRC may be of interest to clarify what is the best treatment strategy in these patients.