DNA sequence comparisons can provide deep insight into phylogenetic relationships, but can also present problems for the unwary. Alignment comparisons are not always as straightforward as they might seem, and comparative models applied to deduce relationships need to be carefully chosen with full regard to the assumptions on which they are based. Most importantly perhaps, genes are not organisms, so some sequence analyses can be poorly informative about relationships - especially if evolution of those organisms has involved significant epigenetic factors, for example, in controlling gene expression. This review highlights some of the most prevalent problems in sequence-based phylogenetic studies of parasite systems.