In order to see the bench-to-bedside dream of translational research become a reality, we develop bio-photonic approaches that, while technologically sophisticated, allow deployment into a clinical setting . Our focus area is where light (an exceptional investigative tool) and patient meet , and improvements that yield better outcomes, by identifying and addressing obstacles preventing the timely clinical adoption of laboratory-based advances. Not the least of these is the difficulty of detecting and characterizing very small entities (molecules, cells) within the human body, especially quantitatively, dynamically, and preferably without contrast agents. How and where we look becomes critically important, especially if one targets (as one should) early diagnosis; for this, new tools and strategies are needed, with likely new outcomes. With lasers heavily featured, we proposed and implemented a multimode  approach to biomedical optical imaging at all levels, featuring hyperspectral imaging, and optimized for earlier, more quantitative and reproducible detection of abnormalities and a tighter spatio-temporal coupling between such diagnosis and intervention. Addressing major areas of unmet need in the clinical realm with these new approaches could yield important improvements in disease management. Our work on superresolution microscopy , and cancer , stem cell , vascular  and neuro (highlighting very early detection of Alzheimer’s Disease)  applications will be described, with emphasis on the new technologies and strategies needed to achieve the desired imaging performance, and their physics and engineering underpinnings. Thoughts  about better ways for academia, the clinical and the corporate world to work together on innovative biophotonic solutions for addressing major disease will be briefly outlined.