show Abstracthide AbstractThe majority of insect herbivores have evolved to colonize a small number of closely related species. Remarkably, the green peach aphid, Myzus persicae, colonizes plant species across 40 families and single M. persicae clonal lineages can colonize distantly related plants. To investigate this exceptional phenotypic plasticity, we sequenced the M. persicae genome and assessed how one clonal lineage responds to host plant species of different families. Aphids have higher numbers of gene expansions than other insect clades. Intriguingly, members of aphid-expanded clades were overrepresented in differentially expressed genes between aphids reared on diverged host plants. The multigene clusters collectively upregulate in single aphids within two days upon host switch. RNA interference (RNAi)-mediated knock-down of cathepsin B genes reduced aphid fitness, but only on the host that induced upregulation of these genes. Thus, lineage-specific gene family expansions and differential regulation of member genes underpin phenotypic plasticity in this widespread clonal lineage.