Within the scope of this laboratory guide it is impossible to give a full review of all the procedures used in the isolation of intact genomic DNA. However, we shall describe a few methods we used which give an excellent quality of both nuclei and DNA suitable for genomic sequencing. Whether we used cells in tissue culture or specific tissues we found that the best quality of DNA was always obtained from isolated nuclei. However, it is also possible to extract large size DNA directly from frozen tissues, cells in tissue culture or protoplasts. Such techniques will be described in detail. If the nuclei are to be used for in vitro footprinting it is important to bear in mind that the salt concentration used during the isolation of nuclei can greatly influence the structure of the chromatin (Lohr, 1986; Walker and Sikorska, 1986) and hence the result of the footprint. In this context we also found that traces of certain detergents such as Triton X-100 can greatly affect the quality of the nuclei. For example the presence of 0.05% Triton X-100 during the preparation of chicken liver nuclei drastically alters the morphology of the nuclei (Fig. II. 1). Such nuclei have an altered chromatin structure and no longer synthesize RNA in vitro. Some cells and tissues contain large amounts of deoxyribonuclease activity; in such cases Mg++ions should be replaced by low concentrations of polyamines.