There are presently a number of different barriers available for use clinically in guided tissue regeneration (GTR) procedures. A number of trials using these techniques and comparing different types of barrier membranes are being published in the scientific literature. This review discusses issues related to clinical trials on the use of barrier membranes in periodontal regeneration. Outcome measures, both clinical and histological, are discussed in relation to results following GTR procedures. The difference between regeneration and repair is reviewed as well as methods of clinical and histologic assessment of both these outcomes. Data regarding the impact of patient variables and tooth or defect variables on outcomes are presented and suggestions for study designs are made based on these variables. Aspects of assessing for an appropriate sample size in superiority and equivalency trials using GTR techniques are presented as well as interpretation of results following these trials and their clinical significance.