Nuclear morphometric descriptors such as nuclear size, shape, DNA content and chromatin organization are used by pathologists as diagnostic markers for cancer. Tumorigenesis involves a series of poorly understood morphological changes that lead to the development of hyperplasia, dysplasia, in situ carcinoma, invasive carcinoma, and in many instances finally metastatic carcinoma. Nuclei from different stages of disease progression exhibit changes in shape and the reorganization of chromatin, which appears to correlate with malignancy. Multistep tumorigenesis is a process that results from alterations in the function of DNA. These alterations result from stable genetic changes, including those of tumor suppressor genes, oncogenes and DNA stability genes, and potentially reversible epigenetic changes, which are modifications in gene function without a change in the DNA sequence. DNA methylation and histone modifications are two epigenetic mechanisms that are altered in cancer cells. The impact of genetic (e.g., mutations in Rb and ras family) and epigenetic alterations with a focus on histone modifications on chromatin structure and function in cancer cells are reviewed here.