Nuclear architecture is extremely complex. The nucleus contains numerous subcompartments in which regulatory factors concentrate; moreover, these are highly dynamic and reorganize as cells divide and differentiate. How such reorganization is linked to regulation of gene expression and other nuclear processes is not clear. Gary Stein and co-workers have therefore developed a systems biology strategy to tackle the problem (see p. 4889). They have combined fluorescence microscopy, image processing and statistical analysis to describe the subnuclear organization of Runx transcription factors. Key parameters in this intranuclear informatics strategy include domain size, domain packing and spatial randomness. The approach reveals characteristic architectural signatures established by wild-type and mutant Runx proteins after mitosis. In addition, the authors are able to correlate these with the biological activities of the proteins and their involvement in disease. Stein and co-workers conclude that the organization of Runx factors within the nucleus is fundamental to their tissue-specific regulatory function. Furthermore, they suggest that intranuclear informatics will be applicable to analysis of other spatially organized nuclear microenvironments.