Poly(ADP-ribose) polymerase 1 (PARP-1) is known to be a crucial part of basic DNA repair machinery, as well as being intimately involved in maintenance of genomic stability. In its main role it binds DNA nicks and breaks, and then adds poly(ADP-ribose) (PAR) chains on histones and other nuclear proteins. This causes relaxation of chromatin and allows other DNA repair proteins access to the site of the lesion. In the case of overwhelming DNA damage, PARP-1 is implicated in generation of a signal that initiates apoptosis. Research has also shown that PARP-1 also binds some other DNA structures (such as junctions and loops), and an increasing body of evidence implicates it in transcription regulation. The fundamental importance of the function of PARP-1 has led to an avalanche of research on its potential uses as a drug target in many areas of medicine, from cancer prevention and treatment, restoration of activity of anticancer drugs in resistant tumors, over prevention of tissue damage from ischemia/reperfusion, to diabetes and asthma treatments. Considering its importance and the amount of research centered on it, it is somewhat surprising that the mechanism of its DNA binding remains largely unknown, along with the question of how and when binding initiates its catalytic activity. Our studies include structure-function analyses of human PARP-1 and its functional domains with respect to their roles in damaged DNA binding.