With the recent completion of the human genome, it has become clear that highly accurate, long reads are critical for the resolution of complex, repetitive genomic loci. Nowhere is this more apparent than the efforts to resolve the extremely polymorphic genes encoding immune receptors. We have developed novel, targeted molecular enrichment methods, paired with single-molecule, real-time (SMRT) sequencing and custom analysis pipelines for haplotype-resolved genotyping and expressed immune receptor characterization for both antibody and T cell receptor profiling in humans, rhesus macaques, and mice. When applied to the largest cohort to date of healthy individuals collected across the globe, we observe an extreme level of structural and single nucleotide variation that is often population specific. These genomic variants, even in non-coding regions, impact antibody genes expression in the circulating repertoire, impacting the development of broadly neutralizing antibodies in the context of vaccination. Moreover, similar extensive variation in the T cell receptor loci influence the development of adverse effects to immunotherapy. These results have direct implications that may explain differential responses to pathogen infection, susceptibility to autoimmunity, and effectiveness of immunotherapy for cancer.