Randomized, controlled clinical trials are prospective studies involving human subjects that are designed to assess disease interventions by comparing end-points related to patient well-being. The purpose of this article is to examine the parameter probing (or pocket) depth as a meaningful end-point for evaluating novel periodontitis therapies. Probing depth provides an estimate of the inflamed, ulcerated lesion secondary to periodontitis disease. Probing depth measurements strongly correlate with the concentrations of host inflammatory mediators implicated in the pathogenesis of periodontitis; these mediators are generated locally secondary to the etiologic biofilm. Probing depth is a well-recognized and routine diagnostic parameter for periodontitis. It is easy to measure and interpret, sensitive to change with treatment, and correlates with other parameters of interest. Evidence from cohort studies indicates that increased probing depth is predictive of periodontitis events such as alveolar bone resorption and tooth loss. Clinical trials assessing probing depth as an efficacy outcome should feature standardization and calibration procedures to decrease measurement bias and variability. In addition, the analysis and presentation of probing-depth data should include the overall population, prognostic subcohorts, and consideration of clinical relevance. Probing depth is the most commonly reported outcome in periodontitis clinical trials and is a meaningful end-point for investigators and clinicians to judge the efficacy of periodontitis interventions.