The ubiquitous Ca2(+)-phosphoinositide pathway transduces extracellular signals to cellular effectors. Using a mathematical model, we simulated intracellular Ca2+ fluctuations in hepatocytes upon humoral stimulation. We estimated the information encoded about random humoral stimuli in these Ca2+ spike trains using an information-theoretic approach based on stimulus estimation methods. We demonstrate accurate transfer of information about random humoral signals with low temporal cutoff frequencies. In contrast, our results suggest that high-frequency stimuli are poorly transduced by the transmembrane machinery. We found that humoral signals are encoded in both the timing and amplitude of intracellular Ca2+ spikes. The information transmitted per spike is similar to that of sensory neuronal systems, in spite of several orders of magnitude difference in firing rate.