The presence of the so-called trace amines 2-phenylethylamine, m-tyramine, p-tyramine, m-octopamine, p-octopamine and tryptamine in the mammalian central nervous system has been known for several decades. Despite much initial interest, these amines have largely been thought of as little more than metabolic by-products. The recent description of a family of mammalian trace amine receptors has, however, seen a resurgence of interest in the physiological role of this class of compounds. Although the trace amines are well documented to cause amphetamine-like effects, such responses only occur at concentrations multiple orders of magnitude above normal physiological levels. As such, it seems unlikely that these responses reflect the true physiological role of the trace amines. In this article previous studies showing responses to physiologically relevant concentrations of trace amines are reviewed, along with those showing a reciprocal relationship between trace amine levels and fluctuations in basal monoaminergic tone. On the basis of these studies it is hypothesized that the trace amines function as endogenous neuromodulators of classical monoamine neurotransmitters. These effects are seen as an altered neuronal sensitivity to monoamine neurotransmitters, with no change in neuronal excitability in the absence of neurotransmitter.