Optical imaging is emerging as a non-invasive and non-ionizing method for breast cancer diagnosis. A hand-held optical imager has been developed with coregistration facilities towards flexible imaging of different tissue volumes and curvatures in near real-time. Herein, fluorescence-enhanced optical imaging experiments are performed to demonstrate deeper target detection under perfect and imperfect (100:1) uptake conditions in (liquid) tissue phantoms and in vitro. Upon summation of multiple scans (fluorescence intensity images), fluorescent targets are detected at greater depths than from single scan alone.