The iris is the most anterior portion of the uveal tract. The pupil is round opening near the center of the iris; it is displaced slightly downward and nasally with respect to the center of the cornea. The mammalian iris sphincter is considered to be innervated by cholinergic, and the dilator muscle by adrenergic excitatory nerve fibers, and both miosis and mydriasis are the result of contraction of the iris sphincter and the dilator muscles due to activation of these excitatory nerve fibers. Pharmacological and histological investigations also reveal that the sphincter muscle is innervated in part by inhibitory adrenergic nerve fibers, and that the dilator muscle is also innervated by inhibitory cholinergic nerve fibers. In addition to the release of acetylcholine and norepinephrine by these nerves, the peripheral nerves to the mammalian iris contain various neuropeptides, although the functional role of these pepetides is not clear. It has been known for more than 100 years that two types of photosensitive cells exist in man. However, some totally blind individuals maintain a normal circadian rhythm. Such a phenomenon cannot be explained by the rod and cone functions. Recently, a new photosensitive pigment, melanopsin, was found in the dermal melanophore cells of the frog. In 2002, melanopsin-containing retinal ganglion cells (mRGCs) were discovered and revealed that mRGCs would depolarize without input from the photoreceptors, meaning that these cells are photosensitive. In the human retina, mRGCs comprise only 0.2% of all ganglion cells. Electrophysiological studies show that light slowly depolarizes mRGCs but rapidly hyperpolarizes rods and cones. The mRGCs innervate the suprachiasmatic nucleus, which is the master circadian pacemaker in mammals, and the olivary pretectal nucleus of the midbrain. In addition to their role in circadian entrainment, the mRGCs mediate the pupillary light reflex. We investigated the mechanism of photoreception by retinal photoreceptor cells, and to evaluate the relative contribution of pupil light response using the control, instigated pharmacological blockade of neurotransmission (PB) model and a transgenic model of retinal degeneration (Tg) rabbit. Although rod and cone photoreceptors disappeared in the PB and Tg models, miosis was still induced during exposure to blue light (470 nm). The greater sustained constriction of pupils to blue light in eyes with outer retinal damage reflects mRGC activation. Our study also indicated that some histologically-identified RGCs were consistent with the characteristics and structures of mRGC. Clinically, in age-related macular degeneration patients, there was no reliable recordable pupil response to red light, even at the brightest intensity but a blue light evoked a sustained pupil constriction. However, in glaucoma patients, there was no reliable recordable pupil response to the brightest intensity of blue light. These preliminary recordings in human subjects demonstrate that changes in the pupil responses to chromatic stimuli are readily detectable and easily quantifiable with standard instruments of clinical testing. We hypothesize that changes in the transient pupil response to red light and low intensity blue light may be more sensitive to cone and rod disease, whereas changes in the sustained pupil response to bright blue light may be more sensitive to optic nerve disease. Ongoing studies of the pupil are aimed at optimizing stimulus conditions that elicit pupil responses that can better localize the site of damage to rods, cones, and RGCs, to quantify the extent of disease.