The distribution and abundance of the greater sage-grouse (Centrocercus urophasianus) have declined dramatically, and as a result the species has become the focus of conservation efforts. We conducted a range-wide genetic survey of the species which included 46 populations and over 1000 individuals using both mitochondrial sequence data and data from seven nuclear microsatellites. Nested clade and structure analyses revealed that, in general, the greater sage-grouse populations follow an isolation-by-distance model of restricted gene flow. This suggests that movements of the greater sage-grouse are typically among neighbouring populations and not across the species, range. This may have important implications if management is considering translocations as they should involve neighbouring rather than distant populations to preserve any effects of local adaptation. We identified two populations in Washington with low levels of genetic variation that reflect severe habitat loss and dramatic population decline. Managers of these populations may consider augmentation from geographically close populations. One population (Lyon/Mono) on the southwestern edge of the species’ range appears to have been isolated from all other greater sage-grouse populations. This population is sufficiently genetically distinct that it warrants protection and management as a separate unit. The genetic data presented here, in conjunction with large-scale demographic and habitat data, will provide an integrated approach to conservation efforts for the greater sage-grouse.