Calcium signalling is involved in myriad cellular processes such as mating morphogenesis. Mating in yeast induces changes in cell morphology with a concomitant increase in calcium uptake that is dependent on the MID1 and CCH1 genes. Mid1p and Cch1p are believed to function in a capacitive calcium entry (CCE)-like process. Amiodarone alters mammalian calcium channel activity but, despite its clinical importance, its molecular mechanisms are not clearly defined. We have shown previously that amiodarone has fungicidal activity against a broad array of fungi. We show here that amiodarone causes a dramatic increase in cytoplasmic calcium ([Ca2+]cyt) in Saccharomyces cerevisiae. The majority of this increase is dependent on extracellular Ca2+ nonetheless, a significant increase in [Ca2+]cyt is still induced by amiodarone when no uptake of extracellular Ca2+ can occur. The influx of extracellular Ca2+ may be a direct effect of amiodarone on a membrane transporter or may be by a CCE mechanism. Uptake of the extracellular Ca2+ is inhibited by caffeine and reduced in strains deleted for the mid1 gene, but not in cells deleted for cch1. Our data are the first demonstrating control of yeast calcium channels by amiodarone and caffeine.