Confocal laser endomicroscopy (CLE) is a new endoscopic imaging tool enabling in vivo histology during ongoing endoscopy. Basically, three different patterns can be seen in the colon: normal, neoplastic and inflammatory mucosa. Several pilot studies have shown an excellent correlation with classical histology. However, what could be the future indications of CLE? (1) Differentiating neoplastic from inflammatory changes constitutes a promising diagnostic tool in screening for dysplasia in ulcerative colitis. This can help to further increase the efficacy of chromoendoscopy in dysplasia detection and reduce the number of biopsies. The possibility to differentiate sporadic adenoma from dysplasia-associated lesion or mass could have an immediate impact on patient management. (2) The diagnosis of collagenous colitis depends on multiple random biopsies. Case series have shown that CLE can guide the endoscopist to take more representative biopsies to make the diagnosis. Large prospective trials are needed to confirm this finding. (3) An interesting clinical application is graft-versus-host disease (GVHD). A pilot study showed that it was possible to predict the presence of GVHD in 14/19 patients with GVHD out of 35 patients who were referred for diarrhea after stem cell transplantation. (4) CLE for standard polyp surveillance is probably redundant since it will not change patient management at this stage. Moreover, it can currently not differentiate between classical hyperplastic and sessile serrated adenomas. (5) Future additional technological improvements of the system with faster Z-scanning, deeper light penetration and 3D reconstruction will help to improve the quality of CLE. Reports on in vivo molecular imaging and assessment of physiological changes provide a promising glance at the future possibilities of CLE imaging.