Although the tear film has been extensively studied as it exists in the open eye state, until recently very little was known as to what happens to the tear film on eye closure. Recent studies have shown that eye closure results in a profound change in the composition, origins, turnover and physiological functions of the tear film. These changes include a shift from an inducible, neurologically controlled, lacrimal secretion containing among other proteins primarily lysozyme, lactoferrin and tear specific lipocalin, to a much slower, constitutive-type of secretion, composed almost exclusively of sIgA. This change is accompanied by the build-up of sialoglycoproteins of epithelial and goblet cell origin, the build-up and activation of complement and the build-up of serum proteins. In addition, various cytokines and proinflammatory mediators accumulate, including some which are potent inducers of angiogenesis and leukochemotaxis. The closed eye also exhibits the recruitment and activation of massive numbers of PMN cells. This results in a stagnant, closed eye layer, which is extremely rich in reactive complement products, PMN cell proteases including protease-3, elastase, capthepsin G, MMP-9 and urokinase. We have postulated that this shift represents a fundamental change in host-defense strategies from a passive-barrier defense to an active immune, inflammatory, phagocyte-mediated process and that this shift is necessitated in order to protect the cornea from entrapped microorganisms. Studies have shown that autologous cell damage is avoided in closed eye tear fluid, by the accumulation of several modulators of complement activation, which shift activation towards opsonization of entrapped microorganisms and the build-up of a wide array of antiproteases. Some of the latter are likely to arise from the ocular surface tissues. Corneal neovascularization may be avoided in part by the build-up of alpha2-macroglobulin and the conversion of plasminogen to angiostatin. It is highly probable that other bioactive protein fragments are produced in the closed eye, which contribute to homeostasis. Areas of future study are indicated.