Genotyping of rare variants on a large scale is now possible using next-generation sequencing. Sample selection is a crucial step in designing the genetic study of a complex disease, and knowledge of the efficiency and limitations of population-based and family-based designs can help researchers make the appropriate choice. The nine contributions to Group 5 of Genetic Analysis Workshop 17 evaluate population-based and family-based designs by comparing the results obtained with various methods applied to the mini-exome simulations. These simulations consisted of 200 replicates composed of unrelated individuals and eight extended pedigrees with genotypes and various phenotypes. The methods tested for association with a population-based and/or a family-based design, tested for linkage with a family-based design, or estimated heritability. We summarize the strengths and weaknesses of both designs. Although population-based designs seem more suitable for detecting the effect of multiple rare variants, family-based designs can potentially enrich the sample in rare variants, for which the effect would be concealed at the population level. However, as of today, the main limitation is still the high cost of next-generation sequencing. Genet. Epidemiol. 35:S41–S47, 2011. © 2011 Wiley Periodicals, Inc.