DNA methylation plays an essential role in the control of gene expression during early stages of development as well as in disease. Although many transcription factors are sensitive to this modification of the DNA, we still do not clearly understand how it contributes to the establishment of proper gene expression patterns. We discuss here the recent findings regarding the biological and molecular function(s) of the transcription factor ZBTB38 that binds methylated DNA sequences in vitro and in cells. We speculate how these findings may help understand the role of DNA methylation and DNA methylation-sensitive transcription factors in mammalian cells.