Non-covalent genotoxic interaction between DNA and classical planar fused-ring intercalating agents, has been well understood for some time especially in the context of frameshift mutagenesis in bacterial systems. Recent evidence, however, suggests that a rather wide structural range of small non-fused ring molecules may also be capable of partial or complete DNA intercalation in mammalian cells. The present paper will review recent studies on the identification and characterization of such atypically-structured molecules utilizing both cell-based and three-dimensional computational analyses focusing principally on prediction and detection of these atypical molecules. Mechanistic aspects of genotoxicity of such non-covalent binding molecules, with emphasis on marketed pharmaceuticals, will also be discussed. A review and presentation of new data using catalytic DNA topo II inhibitors, confirms the notion that topoisomerase II poisoning arising via intercalation is the major mechanism of genotoxicity of these drugs.