Human inherited antibody deficiency disorders are generally caused by mutations in genes involved in the pathways regulating B-cell class switch recombination; DNA damage repair; and B-cell development, differentiation, and survival. Sequencing a large set of candidate genes involved in these pathways appears to be a highly efficient way to identify novel mutations. Herein we review several high-throughput sequencing approaches as well as recent improvements in target gene enrichment technologies. Systematic improvement of enrichment and sequencing methods, along with refinement of the experimental process is necessary to develop a cost-effective high-throughput resequencing assay for a large cohort of patient samples. The Hyper-IgM/CVID chip is one example of a resequencing platform that may be used to identify known or novel mutations in patents with various types of inherited antibody deficiency.