Syncytiotrophoblasts arise from the fusion of cytotrophoblasts, a process regulated by cyclic nucleotide signaling. Syncytiotrophoblasts express transporters, including the multidrug resistance-associated proteins (MRP) 1, 3, and 5, which regulate the intracellular concentration of cyclic nucleotides through active efflux. Understanding the interplay of cyclic nucleotides, efflux transporters, and syncytialization is important because aberrant cytotrophoblast functioning contributes to the pathogenesis of placental diseases. Through pharmacological and genetic loss of function approaches we have shown that MRP transporters participate in trophoblast cell fusion as determined by changes in cell fusion and hormone secretion markers, cell size, and expression of tight junction protein e-cadherin.