Bisphenol A (BPA) and several of its derivatives are widely used to manufacture industrial products such as polycarbonates, polyesters, flame retardants and epoxy resins. These substances are imagined to have adverse effects on human health and development. Here we show that voltage-activated Ca²⁺ channels in cardiac myocytes, DRG neurons, GH₃ cells (L-, N-, P/Q- type) and in HEK293 cells (stably expressing R-type) were rapidly and reversibly blocked by BPA at micromolar concentration (EC₅₀= 26-35 µM). Biophysical analysis of R-type Ca²⁺ channels revealed that BPA interacts with the channel in its resting state by directly binding to the external part of the channel protein outside the pore forming region. Its action is neither voltage- nor use-dependent, and does not affect channel gating nor does it require intracellular pathways. To investigate the structural requirements of BPA to become effective on Ca²⁺ channels we tested various phenolic and bisphenolic compounds. These structure effect analyses revealed that a double alkylated, or double-trifluoromethylated sp³ hybridized carbon atom between the two aromatic rings and the two aromatic moieties in angulated orientation are optimal for BPA´s effectiveness. Our results show that among the bisphenols tested BPA was the most effective compound with the exception of bisphenol AF (BPAF) which was about twice as effective as BPA (EC₅₀= 13 µM). Several related compounds such as bisphenol S (BPS) were almost ineffective. These findings may provide a basis for future research concerning BPA alternatives in plastic production which are harmless to humans and other organisms.