The common bed bug (Cimex lectularius) has been a persistent pest of humans for thousands of years, yet the genetic basis of the bed bug’s basic biology and adaptation to dense human environments is largely unknown. In a large, collaborative effort we sequenced the genome of the bed bug using short (Illumina) and long (Moleculo) read technologies, uncovering a genome size of ~698 Mb harboring ~37,000 genes. Using RNA-seq we uncovered changes in gene expression along the life cycle. The most pronounced differences occurred after feeding on human blood and included genes from the Wolbachia endosymbiont, which shows a simultaneous and coordinated host-commensal response to blood feeding. These data provide a rich genetic resource for mapping activity and density of bed bugs across human hosts and cities, which can help track, manage, and control bed bug infestations.