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Aspergillus fumigatus is an aggressive opportunistic pathogen of humans as well as a major allergen. Environmental sensing and retrieving essential nutrients from the environment are general metabolic traits associated with the growth of this saprophytic fungus. Two important mediators of calcium signals in eukaryotic cells are the Ca2+-binding protein calmodulin and the Ca2+/calmodulin-dependent phosphatase calcineurin. Calcineurin is a heterodimer that consists of a catalytic subunit A and a Ca2+/calmodulin binding unit. We deleted the A. fumigatus calA gene, which encodes the calcineurin A catalytic subunit, and demonstrated that this gene is not essential in this fungus. The ΔcalA mutant strain has severe defects in growth extension, branching and conidial architecture. Furthermore, the A. fumigatus ΔcalA mutant strain has decreased fitness in a low dose murine infection and cannot grow in fetal bovine serum (FBS). After potassium phosphate was added to liquid FBS, the ΔcalA mutant strain could grow with the characteristic phenotype of the ΔcalA mutation. When A. fumigatus calcineurin is inhibited by tacrolimus in a phosphate depleted medium, there is a reduction in the inorganic phosphate transport and six putative phosphate transporter genes have altered mRNA levels. However, there is no effect on the acid phosphatase activity. These results suggest that calcineurin is involved in the regulation of the PHO pathway in A. fumigatus. Our work on calcineurin opens new venues for the research on sensing and nutrient acquisition in A. fumigatus.