Recent advances in understanding the molecular basis of cancer have led to the development of novel targeted therapies. The advantage of these therapies lies in their increased efficiency and reduced adverse events as compared to classicaL chemotherapy. One of these novel treatments is antibodies directed against Epidermal Growth Factor Receptor for colorectal carcinoma (CRC). Apparently, this treatment is only effective in patients whose tumor carries a wild-type copy of KRAS. Therefore, treatment decision in patients with CRC is based on molecular pathoLogical examination of the tumor tissue. Molecular testing for KRAS mutation in CRC carries new challenges. As opposed to germ-line mutations, which are present in all the cells, most of the mutations in cancer are somatic and present only in the tumor cells. This might make the diagnosis more difficult since the tumor tissue contains the tumor cells as well as stromal and inflammatory cells. Choosing an area that contains a smaller fraction of tumor cells might Lead to false negative results in the moLecular diagnosis. Identification of a tumor-rich area by a pathologist, who also determines the tumor cell fraction and chooses a test modality with the required sensitivity, will reduce the risk for such mistakes. Another issue that requires attention is intra-tumor heterogeneity. Recent reports have demonstrated that tumor cell population contains several sub-groups with differences in their mutational status. This phenomenon might affect the treatment choice and patients' response to therapy. However, recent reports in the literature indicate relative homogeneity for KRAS mutational status in CRC. In summary, molecular pathology is a new and rapidly evolving field chaLLenging pathologists involved in cancer diagnosis. It is crucial to make sure that the testing would be carried out in specialized centers that can address the molecular, as well as the histo-pathological aspects of the disease, to allow accurate diagnoses of high quality.