Cell proliferation and differentiation are guided by changes in gene expression and require the coordinated efforts of the transcription machinery and chromatin-remodeling factors. However, aberrant regulation of chromatin structure can arise through mutations in chromatin-modifying and-remodeling proteins and can lead to improper gene expression and cancer. This review discusses how mutations in chromatin regulators might affect their targeting or activity, with an emphasis on the important insights revealed by leukemogenic fusion proteins. Understanding the normal and oncogenic role of these factors will be crucial for the design of therapeutic agents.