Ca2+-calmodulin-dependent phosphodiesterases (PDE1), like Ca2+-sensitive adenylyl cyclases (AC), are key enzymes that play a pivotal role in mediating the cross-talk between cAMP and Ca2+ signalling. Our understanding of how ACs respond to Ca2+ has advanced greatly, with significant breakthroughs at both the molecular and functional level. By contrast, little is known of the mechanisms that might underlie the regulation of PDE1 by Ca2+ in the intact cell. In living cells, Ca2+ signals are complex and diverse, exhibiting different spatial and temporal properties. The potential therefore exists for dynamic changes in the subcellular distribution and activation of PDE1 in relation to intracellular Ca2+ dynamics. PDE1s are a large family of multiply-spliced gene products. Therefore, it is possible that a cell-type specific response to elevation in [Ca2+]i can occur, depending on the isoform of PDE1 expressed. In this article, we summarize current knowledge on Ca2+ regulation of PDE1 in the intact cell and discuss approaches that might be undertaken to delineate the responses of this important group of enzymes to changes in [Ca2+]i.