The biobehavioral phenomena of sleep and cognition involve complex phenotype-genotype associations, i.e., complex relationships between observable traits and the genetic variants that contribute to the expression of those traits. There is a general belief that investigating such relationships requires large sample sizes. However, sleep- and cognition-related phenotype-genotype associations may be strengthened through carefully controlled laboratory studies that amplify a given cognitive phenotype by perturbing the biobehavioral system through sleep deprivation and/or pharmacogenetic interventions. Utilization of performance tasks that dissociate cognitive processes allows for cognitive endophenotyping, that is, making precise measurements that capture the essence of a cognitive phenotype. This enables assessment of the genetic underpinnings of cognitive impairment due to sleep deprivation without necessarily requiring large samples. Theory-driven gene selection, selective population sampling techniques to avoid underrepresentation of rare genetic variants, and modern statistical techniques informed by prior knowledge further enhance statistical power. Here we illustrate these approaches on the basis of recent findings, supplemented with some new results, as well as a discussion of modern regression methods for statistical analysis. Ongoing research employing these methods is driving advancements in the understanding of the genetic underpinnings of cognitive impairment associated with sleep loss.