Zebrafish embryos are an exceptional system for studying vertebrate development. Historically, studies using zebrafish to uncover key players in developmentally regulated gene expression have entailed detailed analysis of transcription factors. It is now apparent that epigenetic modifications of both DNA and histone tails are equally important in the regulation of gene expression during development. As such, blocking the function of key epigenetic modifiers impairs development, albeit with surprising tissue specificity. For instance, DNA methylation is an important epigenetic mark that is depleted in embryos lacking dnmt1 and uhrf1. These embryos display developmental defects in the eye, liver, pancreas, and larval lethality. Interestingly, human tumors derived from these same organs have aberrant changes in DNA methylation and altered expression of genes that are thought to contribute to formation of these cancers. These observations have provided a mechanistic basis for treating cancer with drugs that block the enzymes that facilitate DNA and histone modifications. Thus, it is important to understand the consequences of targeting these factors in a whole animal. We review the use of zebrafish for probing the genetic, cellular, and physiological response to alterations in the epigenome and highlight exciting data illustrating that epigenetic studies using zebrafish can inform and impact cancer biology. Birth Defects Research (Part C) 93:194–203, 2011. © 2011 Wiley‐Liss, Inc.