Dry eye disease is a multifactorial chronic disorder of the ocular surface that affects up to 100 million people worldwide. During the pathogenesis of dry eye, impaired function of the lacrimal and meibomian glands results in hyposecretion of aqueous tear fluid, coupled with increased evaporation and instability of the tear film, which becomes increasingly hyperosmolar in character at more severe stages of disease. One critical issue in the field is that the commonly used clinical signs and symptoms for the diagnosis or classification of dry eye often do not correlate with one another. This underscores the need to systematically evaluate current tests and highlights the importance of developing new markers of disease progression for use as endpoints in clinical trials of diagnostic devices and potential therapeutics. In this review, we examine the utility and limitations of commonly used signs and symptoms of dry eye disease and comment on newer biomarkers and analytical devices that show promise for future diagnostic and therapeutic use.