Genomic tools and analyses are now being widely used to understand genome-wide patterns and processes associated with speciation and adaptation. In this article, we apply a genomics approach to the model organism Drosophila melanogaster. This species originated in Africa and subsequently spread and adapted to temperate environments of Eurasia and the New World, leading some populations to evolve reproductive isolation, especially between cosmopolitan and Zimbabwean populations. We used tiling arrays to identify highly differentiated regions within and between North America (the United States and Caribbean) and Africa (Cameroon and Zimbabwe) across 63% of the D. melanogaster genome and then sequenced representative fragments to study their genetic divergence. Consistent with previous findings, our results showed that most differentiation was between populations living in Africa vs. outside of Africa (i.e., "out-of-Africa" divergence), with all other geographic differences being less substantial (e.g., between cosmopolitan and Zimbabwean races). The X chromosome was much more strongly differentiated than the autosomes between North American and African populations (i.e., greater X divergence). Overall differentiation was positively associated with recombination rates across chromosomes, with a sharp reduction in regions near centromeres. Fragments surrounding these high F(ST) sites showed reduced haplotype diversity and increased frequency of rare and derived alleles in North American populations compared to African populations. Nevertheless, despite sharp deviation from neutrality in North American strains, a small set of bottleneck/expansion demographic models was consistent with patterns of variation at the majority of our high F(ST) fragments. Although North American populations were more genetically variable compared to Europe, our simulation results were generally consistent with those previously based on European samples. These findings support the hypothesis that most differentiation between North America and Africa was likely driven by the sorting of African standing genetic variation into the New World via Europe. Finally, a few exceptional loci were identified, highlighting the need to use an appropriate demographic null model to identify possible cases of selective sweeps in species with complex demographic histories.