The olfactory system is comprised of three major components -receptors which detect and transduce odor information, neurons which transmit information to the brain, and brain where information is decoded and processed. Receptors are located at the apex of the human nasal cavity and are exposed to the outside world. Receptors evolved from a single cell organism whose first functional survival task involved maintaining neutral pH to control cellular homeostasis. This system was the first sense which evolved into what we now call olfaction. This initial task may have involved two interrelated components which acted at the apex, the leading edge of the single cellthe zinc metalloprotein carbonic anhydrase (CA) which was the sensory portion and a primitive form of myosin which was the motor portion. Since this primitive single cell lived in the dark, liquid primeval ooze, it initially obtained nutrition from chemical moieties in its surroundings and no vascular system was required. As cellular activity moved to land, the internal cellular structure became more complex. While the sensory detection process remained in the apical portion of the cell, the motor portion moved to the distal portion. With movement to land multiple cellular organisms developed. Chemical moieties previously impinging on the cell surface were replaced as cells became more complex with development of internal glandular secretions which contained and secreted those chemical moieties required to maintain and preserve these critical receptor systems. Secretions from these glands became what we now know as growth factors. Sensory perception became increasingly complex as cellular organisms became more complex but the initial CA sensory component was maintained phylogenetically. As this initial sensory system developed, it may have become the model for sensory perceptual components of other sensory systems including taste, vision, and audition with the developing CA mechanism acting as their initial sensory event. As receptors became more complex a systematic process may have developed to preserve and differentiate each sensory process but glandular secretions required to maintain each sensory system were maintained phylogenetically. For olfaction these secretions were synthesized mainly in nasal serous glands which acted on stem cells in the olfactory epithelium to preserve and maintain this system. These multiple secretions include trace metals and their associated metalloproteins, cyclic nucleotides, hormones, vitamins, neurotrophins, and cytokines which both stimulate (upregulate) and inhibit (downregulate) this initial receptor system to maintain its homeostatic integration in which blood vessels and lymphatics play no specific role. R.I. Henkin ( )