The literature on thia-Michael acceptors is vast and can be cherry-picked to show either that these compounds pollute chemical libraries displaying unselective binding and propensity to toxicity, or, alternatively, that the thiol-trapping reaction is highly selective and critical for bioactivity. Since the energy of the carbon–sulfur bond (ca 60 kcal/mole) is similar to the one of the π-component of a carbon–carbon double bond, all thia-Michael additions are, in principle, reversible, and basically thermodynamically driven by the difference in energy between an S–H and a C–H bond. However, the rate of the backward reaction can vary dramatically, depending on mesomeric effects, strain, and steric considerations that can substantially lower the kinetic barrier to the forward and backward reactions, while the position of the equilibrium is strongly affected by steric effects. As a result, a pulsed, transient binding reminiscent of a non-covalent interaction can take place. We describe how an NMR assay to identify transient Michael acceptors was serendipitously discovered during an investigation on the migraine-inducing toxic constituents of the headache tree [Umbellularia californica (Hook. & Arn.) Nutt.], and summarize how the assay can also be used to locate thia-Michael acceptor sites in complex natural products, to comparatively evaluate thiol affinity in multi-electrophilic compounds, and to rate mixtures of acceptors according to their reactivity with thiol groups.