The influx of Ca2+ ions through voltage-dependent calcium (CaV) channels links electrical signals to physiological responses in all excitable cells. Not surprisingly, blocking CaV channel activity is a powerful method to regulate the function of excitable cells, and this is exploited for both physiological and therapeutic benefit. Nevertheless, the full potential for CaV channel inhibition is not being realized by currently available small-molecule blockers or second-messenger modulators due to limitations in targeting them either to defined groups of cells in an organism or to distinct subcellular regions within a single cell. Here, we review early efforts to engineer protein molecule blockers of CaV channels to fill this crucial niche. This technology would greatly expand the toolbox available to physiologists studying the biology of excitable cells at the cellular and systems level.