The DNAse foot-printing method starts by focusing on a given region of interest (e.g. a promoter region) and amplifying it by PCR to obtain lots of sample. It then throws in the TF and then the DNAse. The mix is left to stir for a short time and then gel electrophoresis is run to compare the pattern of fragments in a control (no TF) and in the sample. If the TF has bound the sample, it will have protected a stretch of DNA (encompassing some fragments of the control) and thus those fragments will not appear in the sample gel. The fragments can then be cut-out from the gel, purified and sequenced to obtain the sequence of the protected region. This is often used to identify the binding motif of a TF for the first time. The foot-printing will typically resolve the protected region down to 50-100 bp, and the sequence can be then examined for possible TF-binding sites either by eye of using a computer search.

Hydroxyl radical footprinting is almost identical to DNase footprinting, except that it uses hydroxyl radicals to digest non-protected DNA. While hydroxyl radicals yield much better resolution than DNases due to the considerable difference in their sizes, they are also harder and more time consuming to use, and thus this method is seen somewhat infrequently.

A variation of DNAse footprinting in which certain residues are methylated to evidence their role in binding. Similar to site-directed mutagenesis in its ability to designate specific residues as being essential for binding.