Infectious diseases are a major cause of morbidity and mortality worldwide. Streptococcus pneumoniae and Neisseria meningitidis are major causes of severe bacterial disease which can manifest as invasive disease such as bacteraemia and meningitis. Exposure to these pathogens is relatively widespread, yet only a minority of individuals develop invasive disease. A host genetic component to infectious disease susceptibility has been implied from twin and adoptee studies. A role for rare large effect genetic variants in predisposition to infection has been demonstrated through the study of individuals with primary immunodeficiencies. However, a majority of these studies have been undertaken in individuals with a history of recurrent disease or in multi-case families. The relative role of rare genetic variants of moderate to large effect at the population level has not been widely explored. This thesis presents effort made using next generation sequencing methods to identify rare genetic variants that lead to increased susceptibility to bacterial disease focussing on meningococcal disease, pleural infection(empyema), pneumococcal disease and sepsis phenotypes. Using an exome sequencing approach in 13 cases with invasive meningococcal disease, a novel mutation leading to a complement deficiency and increased risk of meningococcal infection was identified and functionally validated in one individual. This mutation in the CFP gene was demonstrated as leading to impaired properdin secretion. Further analysis implicated loss of function mutations in CD4 and ZAP70 as novel loci for meningococcal disease susceptibility. A case control association analysis for sepsis susceptibility highlighted the possible role for small Rho GTPases in sepsis pathology. By aggregating all rare predicted deleterious mutations in a gene, four genes in this pathway, (ROCK2, ARHGAP18, FYN and CDC42BPG) were implicated as having an excess of rare deleterious variants in sepsis samples compared to population controls. A similar approach identified low frequency genetic variants in the CD109 gene as predisposing to empyema susceptibility in children. Finally, preliminary evidence from adult individuals with invasive pneumococcal disease points to a potential role of the RNASE7 gene in invasive pneumococcal disease susceptibility. This association was primarily due to a predicted deleterious missense mutation present in cases and absent in controls. Taken together, these results have identified a number of potential loci with rare variants associated with susceptibility to severe phenotypes of bacterial diseases.