Animal genomes are littered with conserved non-coding elements (CNEs) - most of which represent evolutionarily constrained cis-regulatory sequences - however, it is often not clear why these sequences are so exceptionally conserved, since anecdotal examples have shown that orthologous CNEs can have divergent functions in vivo. In an article recently published in Molecular Biology & Evolution, Ritter et al. compare the functional activities of 41 pairs of orthologous conserved non-coding elements (CNEs) from humans and zebrafish (2010). Interestingly, sequence similarity was found to be a poor predictor of which CNEs had conserved function. In contrast, the authors found that measuring transcription factor binding site change, instead of simple sequence divergence, improves their ability to predict functional conservation. While this set of tested CNEs remains relatively small, these results are encouraging because they suggest that as scientists move from phenomenological measures of CNE evolution to models based explicitly on binding site evolution, the patterns of cis-regulatory evolution observed within animal genomes should become far less mysterious.