The analysis of HLA allele frequencies in various Amerindian populations may shed light on the history of human migrations in the Americas; the overall reduction in the number of alleles relative to non-Amerindian populations and the observation that the same alleles and allelic lineages are "missing" in all Amerindian groups suggests an "Into America" population bottleneck. The identification of previously unreported (and presumably newly arisen) HLA-DRB1 alleles among isolated Amerindian groups, (DRB*0417 in Argentina, *08042 in Ecuador, DRB1*0807 in Brazil, and *0811 in Canada) suggests that these alleles may have been generated since the colonization of the Americas (about 20-30,000 years ago). These observations are difficult to reconcile with the notion, based on the analysis of exon-2 sequences, that most of the human DRB1 alleles are "ancient", that is, predate the divergence of the hominoids (4-7 myr). Recent analyses of DRB1 intron sequences, however, indicate that, although most of the allelic lineages are ancient, the alleles within a lineage (> 90% of the DRB1 alleles) have arisen relatively recently. For DRB1*0807, presumably generated by an Asp to Val change (GAT to GTT) at codon 57, strong selective pressures appear to be in operation, based on the high frequency (23%), and linkage disequilibrium patterns of this allele. The analysis of a complex microsatellite in the second intron in the Ticuna is consistent with the notion that the new Amerindian DR8 alleles arose from DRB1*0802, the only DR8 allele observed in most Amerindian populations.