Protein phylogeny, based on primary amino acid sequence relatedness, reflects the evolutionary process and therefore provides a guide to structure, mechanism and function. Any two proteins that are related by common descent are expected to exhibit similar structures and functions to a degree proportional to the degree of their sequence similarity; but two independently evolving proteins should not. This principle provides the impetus to define protein phylogenetic relationships and interrelate families when possible. In this mini-review, we summarize the computational approaches and criteria we use to establish common evolutionary origin. We apply these tools to define distant superfamily relationships between several previously recognized transport protein families. In some cases, available structural and functional data are evaluated in order to substantiate our claim that molecular phylogeny provides a reliable guide to protein structure and function.