The cyclic nucleotides, cyclic adenosine 3':5'-monophosphate (cAMP) and cyclic guanosine 3':5'-monophosphate (cGMP) or their dibutyryl and monobrominated derivatives, may either increase or decrease morphological transformation of Syrian hamster embryo cells exposed to N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG). The effect on transformation is primarily a function of the parent cyclic nucleotide and the duration of exposure to the nucleotides. At concentrations of 5 mM or larger for a minimum 24-hr exposure cAMP, cGMP, and their congeners reduced the colony-forming ability of nontransformed Syrian hamster embryo cells not exposed to MNNG; however, cGMP and its derivatives caused less toxicity than cAMP or its analogs. cAMP and its monobrominated and dibutyrylated derivatives decreased the transformation frequency associated with MNNG irrespective of whether the various adenylnucleotides were administered before or after MNNG. The greatest inhibitory effect of MNNG-induced transformation was obtained with N6,O2-dibutyryl cyclic adenosine 3':5'-monophosphate followed in order by 8-bromocyclic adenosine 3':5'-monophosphate and cAMP. At equimolar doses, the dibutyryl and brominated analogs of cGMP but not unsubstituted cGMP enhanced transformation when administered prior to exposure of the Syrian hamster embryo cells to MNNG but reduced the transformation frequency when added after MNNG. The enhancing and inhibitory effects of the guanine cyclic nucleotide-induced alteration of MNNG-associated transformation frequencies were dose and time dependent and occurred in the order N6,O2-dibutyryl cyclic guanosine 3':5'-monophosphate greater than 8-bromocyclic guanosine 3':5-'monophosphate much greater than cGMP. Butyric acid neither diminished nor increased MNNG-induced transformation frequency. The latter suggests that butyrate ions formed by metabolism of the cyclic nucleotide analogs were not a factor in the observed alterations of transformation frequency.