Increasing evidence suggests that several components of the metazoan innate immune system have evolved from bacterial genes. Indeed, some bacterial antiphage proteins have been shown to be homologous to components of the human immune system. Here, Whiteley and colleagues report a bacterial antiphage protein that contains a NACHT domain, which is also found in metazoan proteins that mediate immunity and inflammation, such as the nucleotide-binding domain and leucine-rich repeat containing gene family (NLRs). The authors report that this NLR-related protein is widespread in bacteria and has an architecture that is similar to the domain architectures of eukaryotic NACHT proteins, comprising a C-terminal sensor domain, the central NACHT module and an N-terminal effector domain. Moreover, bacterial NACHT proteins were shown to defend against both DNA and RNA phages, with phage infection resulting in the activation of the N-terminal effector domain. The authors also noted that phage infection inhibited the growth of bacteria expressing NACHT proteins, which suggests that phage replication is inhibited via abortive infection. Finally, point mutations that hyperactivate NACHT modules in human cells also hyperactivate NACHT modules in bacteria, which is indicative of a related molecular mechanism of NACHT module activation. Together, the data suggest that metazoan NLRs have been acquired via horizontal gene transfer from bacteria.