Calcium antagonistic drugs block the voltage-dependent Ca2+ slow channels in cardiac muscle and vascular smooth muscle. This effect on slow channels is relatively specific, i.e., some of the drugs (e.g., nifedipine and diltiazem) have almost no effect on other types of ion channels (fast Na+ channels and K+ channels). Some of the drugs (e.g., verapamil and bepridil) slightly depress the fast Na+ channels as well. The order of potency in blocking slow channels is generally: mesudipine greater than or equal to nifed greater than dilt greater than verap greater than bep. The blocking effect on the slow channels is frequency dependent (use-dependent), although the dihydropyridines have a lesser frequency dependence. Elevation of [Ca]o antagonizes the inhibition of Ca2+ influx produced by the drugs; partly mediated by a larger electrochemical driving force for Ca++ influx through unblocked channels. Nifed and dilt are the fastest to reverse upon washout. Verap, D600, and nifed block slow Na+ channels found in early embryonic chick hearts; bep, dilt, and mesud do not. Verap and bep inhibit Ca++ binding to sarcolemma; nifed and dilt do not. The order of uptake into muscle follows their order of lipid solubilities: bep greater than verap greater than nitrend greater than nifedipine greater than dilt. Those drugs that readily permeate into the cell interior have the option of having their primary or second site of action on some intracellular site. For example, verap and D600 may block slow channels by acting on the inner surface of the cell membrane, and bep might also act to depress Ca++ release from the SR.