Genes encoding immune system proteins are often among the most rapidly evolving genes in the genome due to host-pathogen arms race dynamics. Using new annotations and transcriptome sequencing of infected and control (naive) flies across 10 species of Drosophila and the house fly Musca domestica, we show that high rates of novel gene acquisition (by gene duplication and by de novo gene origination) also characterize dipteran immune systems. In the house fly, which occupies an unusually pathogen-rich niche among sequenced dipterans, we use new models of gene family evolution to investigate duplication and loss rates across several different classes of immune-related genes. We demonstrate that genes encoding proteins involved in either pathogen recognition or pathogen killing have been duplicating at a significantly accelerated rate along the M. domestica lineage compared to other dipterans, perhaps as a consequence of its septic habitat. Some of these same proteins also display marked patterns of nonneutral sequence divergence. Comparative post-infection RNA-seq analysis also indicates considerable functional evolutionary divergence among dipteran species. Taken together, our results suggest that changes in gene content, sequence and regulation may play a critical role in host adaptation to pathogen pressure.