Intracellular Ca(2+) release is a versatile second messenger system. It is modeled here by reaction-diffusion equations for the free Ca(2+) and Ca(2+) buffers, with spatially discrete clusters of stochastic IP(3) receptor channels (IP(3)Rs) controlling the release of Ca(2+) from the endoplasmic reticulum. IP(3)Rs are activated by a small rise of the cytosolic Ca(2+) concentration and inhibited by large concentrations. Buffering of cytosolic Ca(2+) shapes global Ca(2+) transients. Here we use a model to investigate the effect of buffers with slow and fast reaction rates on single release spikes. We find that, depending on their diffusion coefficient, fast buffers can either decouple clusters or delay inhibition. Slow buffers have little effect on Ca(2+) release, but affect the time course of the signals from the fluorescent Ca(2+) indicator mainly by competing for Ca(2+). At low [IP(3)], fast buffers suppress fluorescence signals, slow buffers increase the contrast between bulk signals and signals at open clusters, and large concentrations of buffers, either fast or slow, decouple clusters.