Recent studies on a novel technology, denoted confocal laser endomicroscopy (CLE), have altered thinking about the possibilities of endoscopy in the diagnosis and treatment of colorectal cancer. CLE is a new endoscopic tool that allows in vivo histology at subcellular resolution during ongoing endoscopy, and permits subsurface imaging of normal and neoplastic human mucosa. This new technique has unequivocal major implications for the diagnosis and clinical management of patients scheduled for screening or surveillance colonoscopy for colorectal cancer. For instance, CLE allows immediate diagnosis of colonic neoplasias, and the detection of neoplastic cells helps to target endoscopic intervention to relevant areas. Furthermore, the combination of chromoendoscopy with CLE significantly decreases the number of biopsies required for cancer surveillance in patients with ulcerative colitis, but provides a fourfold higher diagnostic yield compared with white-light endoscopy used with random biopsies. Taken together, CLE has led colorectal cancer endoscopy into a new era. CLE can no longer be regarded as just another endoscopic technique, but emerges as a crucial novel imaging technique for in vivo diagnosis of colorectal cancer.