Bile duct cancers are increasing in frequency while being difficult to diagnose. Currently available endoscopic imaging devices used in the biliary tree are low resolution with poor image quality, leading to inadequate evaluation of indeterminate biliary strictures. However, a new ultrathin and flexible cholangioscope system has been successfully demonstrated in a human subject. This mini-cholangioscope system uses a scanning fiber endoscope (SFE) as a forward-imaging guidewire, dimensions of 1.2-mm diameter and 3-m length. Full color video (500-line resolution at 30Hz) is the standard SFE imaging mode using spiral scanning of red, green, and blue laser light at low power. Image-guided operation of the biopsy forceps was demonstrated in healthy human bile ducts with and without saline flushing. The laser-based video imaging can be switched to various modes to enhance tissue markers of disease, such as wide-field fluorescence and enhanced spectral imaging. In parallel work, biochemical discrimination of tissue health in pig bile duct has been accomplished using fiberoptic delivery of pulsed UV illumination and time-resolved auto-fluorescence spectroscopic measurements. Implementation of time-resolved fluorescence spectroscopy for biochemical assessment of the bile duct wall is being done through a secondary endoscopic channel. Preliminary results indicate that adequate SNR levels (> 30 dB) can be achieved through a 50 micron fiber, which could serve as an optical biopsy probe. The SFE is an ideal mini-cholangioscope for integration of both tissue and molecular specific image contrast in the future. This will provide the physician with unprecedented abilities to target biopsy locations and perform endoscopically-guided therapies. © 2012 SPIE.