1. The effects of low concentrations of Cs(+) (0.01-3mM) on the fully activated I-V relation ī(f)(E) for the pace-maker current in calf Purkinje fibres have been investigated. The action of Cs(+) is two-fold: in the negative region of the I-V curve Cs(+) induces a channel blockade; on the other hand, at more positive potentials Cs(+) can produce the opposite effect, i.e. a current increase.2. Cs(+)-induced blockade is concentration- and voltage-dependent, as observed on other cation channels. Data in the far negative voltage range (about - 150 to - 50 mV) can be fitted by a simple block model (Woodhull, 1973), which gives a mean value of 0.71 for the fraction of membrane thickness (delta) crossed by Cs(+) ions before reaching the blocking site. The value of delta does not appear to be affected by either external Na or external K concentrations. Values for the dissociation constant of the blocking reaction at E = 0 mV (k(0)) are found in the range 0.5-3.7 mM. In the positive region of the ī(f)(E) relation the current depression caused by channel blockade vanishes. Unexpectedly, in this range the current can be observed to increase with Cs(+), and ī(f)(E) curves in different Cs(+) concentrations show cross-over.3. Changing external K(+) also produces similar cross-over phenomena. Investigation of this effect reveals that the increase in slope of the I-V curve on raising the external K(+) concentration follows Michaelis-Menten kinetics, and can be interpteted in terms of K(+)-induced channel activation. It is found that 44+/-6 mM-K(+) half-saturates the channel activating reaction.4. The Cs(+)-induced current increase is large in low-K(+) solutions and vanishes in high-K(+) solutions, suggesting a competition between Cs(+) and K(+) ions in their activating action. Increasing Na(+) also limits the Cs(+)-induced current increase.5. Rb(+) also blocks the i(f) channel, though less efficiently than Cs(+). The block caused by Rb(+) is, unlike that of Cs(+), nearly voltage-independent, and is explained by assuming that the blocking reaction occurs near the external mouth of the channel (mean value of delta is 0.05). The zero-voltage dissociation constant (k(0)) of the Rb(+)-blocking reaction ranges between 1.4 and 5.4 mM, and is lower in low-Na(+), high-K(+) solutions.6. A possible characterization of the i(f) channel which explains these results includes an inner ;blocking' site, to which external Cs(+) ions bind, blocking the channel, and a more external ;activatory' site, to which K(+), Cs(+), Rb(+) and possibly Na(+) ions bind. Binding of K(+) to this site induces a current increase either by modulating the channel, or actually by opening the channel itself. A similar mechanism can apply to Cs(+) and to Rb(+) binding.