Biophotonics is an emerging field in modern biomedical technology that has opened up new horizons for transfer of state-of-the-art techniques from the areas of lasers, fiber optics and biomedical optics to the life sciences and medicine. This field continues to vastly expand with advanced developments across the entire spectrum of biomedical applications ranging from fundamental “bench” laboratory studies to clinical patient “bedside” diagnostics and therapeutics. However, in order to translate these technologies to clinical device applications, the scientific and industrial community, and FDA are facing the requirement for a thorough evaluation and review of laser radiation safety and efficacy concerns. In many cases, however, the review process is complicated due the lack of effective means and standard test methods to precisely analyze safety and effectiveness of some of the newly developed biophotonics techniques and devices. There is, therefore, an immediate public health need for new test protocols, guidance documents and standard test methods to precisely evaluate fundamental characteristics, performance quality and safety of these technologies and devices. Here, we will overview our recent developments of novel test methodologies for safety and efficacy evaluation of some emerging biophotonics technologies and medical devices. These methodologies are based on integrating the advanced features of state-of-the-art optical sensor technologies and approaches such as high-resolution fiber-optic sensing, confocal and optical coherence tomography imaging, and infrared spectroscopy. The presentation will also illustrate some methodologies developed and implemented for testing intraocular lens implants, biochemical contaminations of medical devices, ultrahigh-resolution nanoscopy, and femtosecond laser therapeutics.