The presence of paired or multiple organs (arches, quadrants, teeth) and the chronic nature of many dental diseases suggest the use of split-mouth (trials in which each subject receives greater than or equal to 2 treatments, each to a separate section of the mouth) and cross-over research designs (trials in which each subject receives greater than or equal to 2 treatments in sequence). While these designs offer potential savings in resources, their usefulness can be negated if several strict scientific and statistical assumptions are not met. The primary prerequisites for the use of split-mouth and cross-over designs are that: (1) the disease to be investigated is relatively stable and uniformly distributed; (2) the effects of the treatments to be evaluated are short-lived or reversible for cross-over studies, or are localized for split-mouth designs. Other important factors that influence the appropriate use of these designs include: the method of treatment sequencing and assignment, and the cross-over rules used; blinding of patient assignment, patients and observers; assessment of order effects including period, carry-over or spill-over effects; the choice of statistical analysis, the sample size utilized, and the special importance of patients lost to study or of faulty data points. The objective of this study was to review 3 journals for studies using split-mouth or cross-over designs to determine how the assumptions underlying these research designs are considered and applied in dental research. The majority of studies used adequate methods for treatment allocation and sequencing; however, many studies failed to take advantage of the research designs in the statistical analysis of data. In addition, very few studies considered the possibility of order effects or reduced bias through blinding procedures.