The ability to obtain reliable results from clinical trials of therapies for ocular allergic disease and dry eye disease is often limited because of inadequate control of variables, such as environment, patient life style, compliance, and individual fluctuations that occur from one assessment visit to another. The controlled allergen challenge (CAC) model of allergic conjunctivitis allows signs and symptoms of the disease to be elicited in a physiologically accurate and reproducible manner. The rigid criteria for subject selection, the controlled allergic reaction, and the standardized and quantified grading systems allow for a reproducible baseline from which statistically and clinically significant differences between formulations can be assessed. Similarly, the controlled adverse environment (CAE) model for dry eye mimics the environmental stimuli that lead to ocular surface drying. Preselected subjects have a reproducible, homogeneous baseline reaction from which the effects of various treatments can be significantly evaluated and compared. CAC and CAE provide accurate means to study highly variable and individual ocular surface disease.