Since the earliest days of civilization, point-of-care testing was performed by physicians in a very rudimentary way to diagnose ailments and illnesses in patients. Although the methods used were crude, the demand for these services highlighted the great need for cheap, rapid, and reliable diagnosis methods at the patient’s location. Optical sensors serve this purpose quite well due to their portability, cost efficiency, and reliability, needing seldom more than eyesight to obtain a quick diagnosis. Due to the simplicity of the sensing mechanism, this method can be translated quite easily into portable instrumentation such as smartphone-based sensing, lab-on-a-chip devices, and paper-based assays. This is very useful due to the need for affordable, rapid, on-site testing in fields such as medical diagnostics and environmental monitoring, particularly in the Global South. In this chapter, we will discuss the fundamental principles of optical response and detection, current methods used for optical sensing in point-of-care applications, and innovations being made to improve the field of optical point-of-care testing. Emphasis will be placed on the different methods of detecting optical responses to stimuli, integrating these sensing methods into portable devices, novel developments in the field of optical point-of-care devices, and challenges that lie ahead.