Histones are involved in DNA compaction and functioning in multi-cellular organisms. In particular, RNA synthesis by RNA polymerase II is typically accompanied by histone survival (via “nucleosomal cycle”) and maintenance of histone-associated regulatory “code” (patterns of covalent histone modifications). Nucleosomal cycle is a complex process that is essential for normal aging and cell functioning; its malfunction results in different types of cancer. Recently we have studied the nucleosomal cycle and the role of various factors in this process using a combination of biochemical, time-resolved and structural approaches. The data suggest that structures of key intermediates formed during the cycle determine the rate and the primary outcomes of the process. Various factors (including hFACT and hPARP1) strongly affect DNA-histone interactions and thus modify the rate and outcomes of the cycle. The role of factor FACT in nucleosomal cycle and tumor development will be discussed.