As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full rangeof the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor forinferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in thestudied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals arenecessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However,by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possibleto reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) inextended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approachesand WGS in unrelated individuals. This was our impetus for forming the “Pedigree-Based Whole Genome Sequencing of Affectiveand Psychotic Disorders”consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatricgenetics research. We begin with a focused review of the current literature, followed by a short history of family-based research inpsychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studyingthe environment, and endophenotypes. We conclude with a brief description of our consortium and its goals.