There have been numerous reports describing the phenomena of low-level light therapy (LLLT) within the clinic and its broad application to alleviate pain, enhance the rate of wound healing, including spinal cord injury, reduce inflammation, improve learning, bolster immunity and combat disease. Yet, despite the breadth of potential applications for which bio-stimulation may prove beneficial, there persists a dramatic ignorance in our understanding of the signal pathways that govern these effects. At the cellular level, there exist a variety of endogenous chromophores such as cytochrome c oxidase, NADPH, FAD, FMN and other factors intrinsic to the electron transport chain in mitochondria that absorb light of specific wavelength and will undoubtedly have their role in bio-stimulation, however the dose dependency of effect with regard to total light fluence and fluence rate, as well as the importance of specific subcellular targeting, remains elusive. Furthermore, the translation of cellular response(s) in vitro to in vivo needs to be expounded. Clearly, a rigorous examination of bio-stimulatory parameters as a function of cellular and tissue response is necessary if we are to attain optimized, reproducible protocolsbasedonatrue scientific rationale for using bio-stimulation as a therapeutic modality in clinic. This paper introduces a number of the challenges we now face for advancing the bio-stimulation phenomena into the scientific mainstream by highlighting our current knowledge in this field as well as some of the research that we are conducting using LLLT in combination with photodynamic therapy.