This review describes the impact of contact lens wear on the tear film lipid layer and how changes in the lipid layer might modulate contact lens-related discomfort. Relevant clinical, functional, and biochemical aspects of the tear film lipid layer are reviewed. Contact lens wear modulates these aspects of the lipid layer, specifically the prelens lipid layer thickness is reduced; tear evaporation rate is increased; tear breakup time is reduced; and the concentration of lipid components such as cholesterol esters, wax esters, and phospholipids varies. The full implications of these changes are unclear; however, there is some evidence that contact lens-related discomfort is associated with a thinner prelens lipid layer, increased lipid degradation, and greater secretory phospholipase A2 activity. Certain fatty acids appear to be associated with maintaining the structural stability of the tear film but their role in retarding tear evaporation and modulating contact lens-related discomfort remains to be elucidated.