Abstract: The role of rare genetic variation in the etiology of complex disease and the optimal study design for identifying rare variants remains unclear. However, the development of next generation sequencing technologies offers the experimental opportunity to address these questions. Several novel statistical methodologies have been recently proposed to assess the contribution of rare variation to complex disease etiology. Nevertheless, no empirical estimates comparing their relative power are available, and the magnitude of the contribution of very rare variants to the statistical power of gene-based association tests is unknown. We therefore assessed the parameters that influence their statistical power in 1,998 individuals Sanger-sequenced at seven genes by modeling different distributions of effect, proportions of causal variants, and direction of the associations (deleterious, protective, or both) in simulated continuous trait and case/control. Our results demonstrate that the power of recently proposed statistical methods depend strongly on the underlying hypotheses concerning the relationship of phenotypes with each of these three factors. As vary rare variants constitute the majority of variants identified in sequencing studies, these findings suggest that careful attention need to be placed on the plausible relationship that exist between very rare variants and common disease. Sensitivity analyses are therefore recommended to compare the stability of the results arising from different methods, and promising results should be replicated using the same method in an independent sample. These findings provide guidance in the analysis and interpretation of the role of rare base-pair variation in the etiology of complex traits and diseases.