A primary focus within biological anthropology has been to elucidate the processes of evolutionary adaptation. Frisancho helped to move anthropology towards more mechanistic explanations of human adaptation by drawing attention to the importance of the functional relevance of human variation. Using the natural laboratory of high altitude, he and others asked whether the unique physiology of indigenous high-altitude residents was the result of acclimatization, developmental plasticity, and/or genetic adaptation in response to the high-altitude environment. We approach the question of human adaptation to high altitude from a somewhat unique vantage point; namely, by examining physiological characteristics—pregnancy and pregnancy outcome—which are closely associated with reproductive fitness. Here we review the potent example of high-altitude native population's resistance to hypoxia-associated reductions in birth weight, which is often associated with higher infant morbidity and mortality at high altitude. With the exception of two recent publications, these comparative birth weight studies have utilized surnames, self-identification, and/or linguistic characteristics to assess ancestry, and none have linked ‘advantageous’ phenotypes to specific genetic variations. Recent advancements in genetic and statistical tools have enabled us to assess individual ancestry with higher resolution, identify the genetic basis of complex phenotypes and to infer the effect of natural selection on specific gene regions. Using these technologies our studies are now directed to determine the genetic variations that underlie the mechanisms by which high-altitude ancestry protects fetal growth and, in turn, to further our understanding of evolutionary processes involved in human adaptation to high altitude. Am. J. Hum. Biol., 2009. © 2009 Wiley-Liss, Inc.