Phosphodiester and phosphorothioate oligodeoxynucleotides are polyanions that cannot passively diffuse across cell membranes. Instead, the processes of adsorbtive endocytosis and pinocytosis probably account for the great majority of oligodeoxynucleotide internalization in most cell types. Oligodeoxynucleotides can adsorb to heparin-binding, cell surface proteins. An example of such a protein is the integrin Mac-1 (alpha M beta 2; CR3; CD11b/CD18), a receptor for fibrinogen which is found on neutrophils, macrophages and natural killer cells. Up-regulation of neutrophil cell surface Mac-1 expression by interleukin 8, arachidonic acid or tumour necrosis factor alpha leads to increased cell surface oligodeoxynucleotide binding and internalization. Binding and internalization can be blocked by both fibrinogen and by anti-Mac-1 monoclonal antibodies. Subsequent to internalization, oligodeoxynucleotides reside in subcellular vesicular structures, i.e. endosomes and lysosomes. However, in the absence of permeabilizing agents, these compartments may be sites of sequestration and the oligomers may be unavailable for antisense activity. At present, controversy surrounds the use of guanosine-rich phosphorothioate oligodeoxynucleotides as antisense agents. We examined the ability of the 24mer antisense rel A (p65) phosphorothioate oligodeoxynucleotide to inhibit nuclear translocation of NF kappa B in K-BALB murine fibroblasts. 7-Deaza-2'-deoxyguanosine substitution in the 5' guanosine quartet region demonstrated that inhibition of nuclear translocation could not be due to a Watson-Crick antisense effect. Rather, we favour the explanation that the parent molecule may be a sequence-specific, apatameric decoy.