Tear lipocalin is a primate protein that was recognized as a lipocalin from the 
homology of the primary sequence. The protein is most concentrated in tears and 
produced by lacrimal glands. Tear lipocalin is also produced in the tongue, 
pituitary, prostate, and the tracheobronchial tree. Tear lipocalin has been 
assigned a multitude of functions. The functions of tear lipocalin are 
inexorably linked to structural characteristics that are often shared by the 
lipocalin family. These characteristics result in the binding and or transport 
of a wide range of small hydrophobic molecules. The cavity of tear lipocalin is 
formed by eight strands (A-H) that are arranged in a β-barrel and are joined by 
loops between the β-strands. Recently, studies of the solution structure of tear 
lipocalin have unveiled new structural features such as cation-π interactions, 
which are extant throughout the lipocalin family. Lipocalin has many unique 
features that affect ligand specificity. These include a capacious and a 
flexible cavity with mobile and short overhanging loops. Specific features that 
confer promiscuity for ligand binding in tear lipocalin will be analyzed. The 
functions of tear lipocalin include the following: antimicrobial activities, 
scavenger of toxic and tear disruptive compounds, endonuclease activity, and 
inhibition of cysteine proteases. In addition, tear lipocalin binds and may 
modulate lipids in the tears. Such actions support roles as an acceptor for 
phospholipid transfer protein, heteropolymer formation to alter viscosity, and 
tear surface interactions. The promiscuous lipid-binding properties of tear 
lipocalin have created opportunities for its use as a drug carrier. Mutant 
analogs have been created to bind other molecules such as vascular endothelial 
growth factor for medicinal use. Tear lipocalin has been touted as a useful 
biomarker for several diseases including breast cancer, chronic obstructive 
pulmonary disease, diabetic retinopathy, and keratoconus. The functional 
possibilities of tear lipocalin dramatically expanded when a putative receptor, 
lipocalin-interacting membrane receptor was identified. However, opposing 
studies claim that lipocalin-interacting membrane receptor is not specific for 
lipocalin. A recent study even suggests a different function for the membrane 
protein. This controversy will be reviewed in light of gene expression data, 
which suggest that tear lipocalin has a different tissue distribution than the 
putative receptor. But the data show lipocalin-interacting membrane receptor is 
expressed on ocular surface epithelium and that a receptor function here would 
be rational.