Histones are now regarded as integral and dynamic components of the machinery responsible for regulating gene transcription. Many types of cancer and other diseases are associated with translocations or mutations in chromatin-modifying enzymes and regulatory proteins. Much of the work in our laboratory has focused on identifying novel histone H3 kinases and the role of histone H3 phosphorylation in cell proliferation and transformation. We are beginning to unravel the complexities of gene expression mediated by histone H3 phosphorylation, which is induced by a whole host of diverse stimuli. Dissimilar cells respond differentially to distinct stimuli, and induction of gene expression is dependent on the type of stimuli, duration and strength of stimuli, state of the cell and of course, specific cell type. Thus, regulation of histone modifications and resultant gene expression is not just one- or two-dimensional but multidimensional, encompassing a huge array of factors. Significant findings such as the observation that histone H3 phosphorylation (Ser10) is critical for neoplastic cell transformation suggests that histone H3 may be a crucial target for cancer chemotherapy or genetic therapy in the future. © 2006 Wiley-Liss, Inc.