Bloodstream infections (BSIs) are a major burden in health care today, associated with considerable morbidity, mortality and costs. They are either caused by direct influx of pathogens via devices into the blood (primary BSI) or by bacterial spillover from infected distant organs (secondary BSI). The recognition of invading microbes by sensing of conserved molecular patterns is pivotal for the host in staging an adequate immune response to eradicate the pathogen. Moreover, a balanced immune response is crucial to avoid over inflammation followed by additional damage to the host. This complex host response pattern is controlled by soluble proteins and cellular receptors, which have recently been found to contain substantial individual genetic variations. Single nucleotide polymorphisms have been shown to affect susceptibility to and the course of numerous diseases. A large number of genes and their products are involved in the host reaction to BSIs, and genetic variation in these molecules alters the frequency and course of these events. Here we summarise recent findings on genetic variations in molecules of the innate immune system and other systems as well as their connection with susceptibility to BSIs and sepsis and the way the host stages a beneficial response to infection.