Genes encoding many of the so-called drug-metabolizing enzymes (DMEs) are present in both prokaryotes and eukaryotes, suggesting that these genes arose on this planet more than 3.5 billion years ago--long before animal-plant divergence (estimated to be about 1.2 billion years ago) and long before the use and commercial development of drugs. What, therefore, are the real functions of DMEs? Several years ago I proposed that DMEs are upstream in the regulatory cascade of numerous signal transduction pathways, i.e. necessary for maintaining physiologically "safe", or "acceptable", steady-state levels of all small non-protein endogenous ligands (M(r) = 250 +/- 200) in each cell. Innumerable foreign chemicals and drugs mimic these small endogenous ligands, thus binding to a particular receptor and acting either as an agonist or antagonist in activating or inhibiting genes effecting growth, differentiation, apoptosis, homeostasis and neuroendocrine functions. Discussed in this review are additional examples consistent with this theory and not described in previous reviews, including: (i) insect-plant symbiosis; (ii) "cross-talk" amongst genes in the aromatic hydrocarbon-responsive [Ah] battery; (iii) signal transduction pathways involving the arachidonic acid cascade; and (iv) the explanation in carcinogen-screening studies as to why a maximum, or half maximum, tolerated dose (MTD, MTD50) of many test compounds might cause cell division and tumorigenesis in experimental animals.