In fungi, genes required for synthesis of secondary metabolites are often clustered. The FUM gene cluster is required for synthesis of fumonisins, a family of toxic secondary metabolites produced by species in the Fusarium (Gibberella) fujikuroi species complex (FFSC). Fumonisins are a health and agricultural concern because their consumption is epidemiologically associated with cancer and neural tube defects in humans and other animals. Among FFSC species, the FUM cluster is uniform in gene order and orientation, but located in different genomic positions. Phylogenetic analyses indicated discord between species phylogenies and FUM gene-based phylogenies. Subsequent constraint analyses confirmed the discord, and analyses of variation in synonymous sites indicated that cluster divergence predated, in some cases, and postdated, in one case, divergence of lineages of Fusarium in which the cluster occurs. The results are not consistent with the discord resulting from transspecies evolution of ancestral cluster alleles, or with interspecies hybridization, but are consistent with duplication of the cluster within an FFSC ancestor and subsequent loss and sorting of paralogous clusters in a manner consistent with the birth-and-death evolution seen in several multigene families. Although the results are also consistent with horizontal transfer of the cluster, such a model is less parsimonious because it requires multiple transfer events from unknown but related donors to multiple FFSC recipients. However, the analyses do provide strong support for horizontal transfer of the cluster from FFSC to another Fusarium lineage. Thus, despite conservation of gene organization within it, the FusariumFUM cluster has had a complex evolutionary history