Infectious diseases are among the leading causes of human morbidity and mortality, with the greatest burden felt in the pediatric population. For any infectious disease, only a fraction of the exposed individuals develop clinical symptoms. These inter-individual differences can be due to variation in pathogen virulence or in host susceptibility. The recent advent of high-throughput sequencing (HTS) technology has enabled studies of both human and pathogen genetic factors that have the potential to influence infectious diseases pathogenesis and alter clinical presentation. In this thesis, I present a set of genomic studies that used HTS to dissect the genetic basis of life-threatening infections with Pseudomonas aeruginosa (P. aeruginosa) and respiratory syncytial virus (RSV). This work provides conclusive evidence for the role of rare human genetic variants in susceptibility to life-threatening P. aeruginosa and RSV infections in previously healthy children. Furthermore, in an attempt to determine the role of viral genetic factors in severe presentations of RSV infection, I established a framework for exploring RSV genetic variation using HTS technology and bioinformatic analysis. Together, theses studies demonstrate that current genomic technology, bioinformatic analysis and functional follow-up have the potential to give us novel insight into the molecular basis of host-pathogen interactions and infectious disease pathogenesis.