Expressed sequence tag (EST), proteomic, and antibody capture assays are revealing a level of tear film protein complexity far greater than previously appreciated. A systems biology approach will be needed to fully appreciate function as tear protein doses fluctuate in time through different conditions. Although consensus is growing on what fully constitutes the human tear proteome, questions remain about the source and significance of the ∼256 tear proteins designated as "intracellular." Many of these may derive from normal cellular turnover and could therefore be informative. A further >183 are designated as "extracellular." Surprisingly, only 4 to 5% of these appear to be dysregulated in the three forms of dry eye preliminarily examined to date. Some differ and a couple overlap, suggesting that disease-specific signatures could be identified. Future dry eye treatment might include recombinant tear protein rescue as a personalized ophthalmic approach to ocular surface disease. © 2008 American Academy of Optometry.