NACHT- and Leucine-Rich-Repeat-containing domain (NLR) proteins act as cytoplasmic sensors for pathogen- and danger-associated molecular patterns and are found throughout the plant and animal kingdoms. In addition to having a small set of conserved NLRs, the genomes in some animal lineages contain massive expansions of this gene family. One of these arose in fishes, after the creation of a gene fusion that combined the core NLR domains with another domain used for immune recognition, the PRY/SPRY or B30.2 domain. We have analysed the expanded NLR gene family in zebrafish, which contains 368 genes, and studied its evolutionary history. The encoded proteins share a defining overall structure, but individual domains show different evolutionary trajectories. Our results suggest gene conversion homogenizes NACHT and B30.2 domain sequences among different gene subfamilies, however, the functional implications of its action remains unclear. The majority of the genes are located on the long arm of chromosome 4, interspersed with several other large multi-gene families, including a new family encoding proteins with multiple tandem arrays of Zinc fingers. This suggests that chromosome 4 may be a hotspot for rapid evolutionary change in zebrafish.