Survival in hyperarid deserts is a major challenge for life in general and for plants in particular. The Atacama Desert presents harsh conditions such as limited rainfall, crusted soils, high soil salinity, high altitude, and intense solar radiation. These conditions, together with paleoclimatic variations over the last 10 million years, have influenced the genetic structure and connectivity of plant populations, resulting in a diverse flora with high endemism. However, the diversification of most lineages appears to be relatively recent, in contrast to the reported age of the Atacama Desert and the onset and expansion of hyperarid conditions since the late Oligocene and early Miocene. A prominent exception is Huidobria chilensis (Loasaceae), which is thought to be endemic to the Atacama since the Eocene. However, it is still not understood why this plant has been successful in adapting to the harshening environmental conditions. To investigate its genetic structure in relation to the history of the Atacama Desert, we studied 186 individuals from 11 populations using genotyping-by-sequencing (GBS). A total of nearly 56 k genome-wide single nucleotide polymorphisms (SNPs) were analyzed for population structure and genetic diversity. We identified four genetic clusters corresponding to geographic regions: the coastal region south of Tocopilla, the Cordillera de la Costa around Chanaral, and the Copiap<acute accent>o catchment 1 and 2. Genetic diversity within and between these clusters was analyzed along with rainfall, altitude, soil composition and landscape data. Although the genetic data support `isolation by distance' as a major factor for genetic divergence between populations, the study also reveals the influence of topography on the distribution of H. chilensis and highlights the role of hydrologically connected watersheds and rivers in plant migration and colonization. Soil composition appears to have a negligible influence. Hence topography and hydrology shape the species' evolutionary trajectory and genetic diversity. Understanding these patterns in H chilensis lets one draw general conclusions about adaptation and survival strategies of plants in extreme desert environments such as the Atacama