From a public health perspective, the “All of Us” study provides an opportunity to isolate targeted and cost-effective prevention and early-detection strategies. Identifying motivations for participation in large-scale genomic sequencing (LSGS) studies, and motivations and preferences to receive results will help determine effective strategies for “All of Us” study implementation. This paper offers a critical review of the literature regarding LSGS for adult onset hereditary conditions where results could indicate an increased risk to develop disease. The purpose of this review is to synthesize studies which explored peoples’ motivations for participating in LSGS studies, and their desire to receive different types of genetic results. Participants were primarily motivated by altruism, desire to know more about their health, and curiosity. When asked about hypothetically receiving results, most participants in hypothetical studies wanted all results except those which were uncertain (i.e., a variant of uncertain significance (VUS)). However, participants in studies where results were returned preferred to receive only results for which an intervention was available, but also wanted VUS. Concerns about peoples’ understanding of results and possible psychosocial implications are noted. Most studies examined populations classified as “early adopters,” therefore, additional research on motivations and expectations among the general public, minority, and underserved populations is needed.