The underlying science of pulse oximetry is based on a simple manipulation of the Lambert-Beer law, which describes the attenuation of light traveling through a mixture of absorbers. Signals from detected red and infrared light that has traveled through blood-perfused tissues are used to estimate the underlying arterial hemoglobin oxygen saturation. However, light scatters in tissue and influences some of the simplifications made in determining this relationship. Under most clinical circumstances, the empirical process that manufacturers use to calibrate the system during its design readily accommodates this and results in accurate readings. The same tissue light scattering properties allow sensors to be configured for use on opposing or adjacent surfaces, provided that the placement sites offer sufficient signal strength and are absent factors known to influence accuracy. In this paper I review the light-tissue interaction in pulse oximetry and describe some of the assumptions made and their implications. Certain deviations from the nominal conditions, whether clinical in nature or misuse of the product, can affect system performance. Consequently, users should be cautious in modifying sensors and/or using them on tissue sites not intended by the manufacturer (off-label use). While perhaps helpful for obtaining pulsatile signals or extending the lifetime of a sensor, some practices can disrupt the optical integrity of the measurement and negatively impact the oxygen saturation reading accuracy.