Postpartum mood disorders develop shortly after childbirth in a significant proportion of women. These conditions are associated with a range of symptoms including abnormally high or low mood, irritability, cognitive disorganisation, disrupted sleep, hallucinations/delusions, and occasionally suicidal or infanticidal ideation; if not treated promptly, they can substantially impact upon the mother's health, mother-infant bonding, and family dynamics. The biological precipitants of such disorders remain unclear, although large changes in maternal immune and hormonal physiology following childbirth are likely to play a role. Pharmacological therapies for postpartum mood disorders can be effective, but may be associated with side effects, concerns relating to breastfeeding, and teratogenicity risks when used prophylactically. Furthermore, most of the drugs that are used to treat postpartum mood disorders are the same ones that are used to treat mood episodes during non-postpartum periods. A better understanding of the biological factors predisposing to postpartum mood disorders would allow for rational drug development, and the identification of predictive biomarkers to ensure that 'at risk' mothers receive earlier and more effective clinical management. We describe new findings relating to the role of the enzyme steroid sulfatase in maternal postpartum behavioural processes, and discuss how these point to a novel molecular risk pathway underlying postpartum mood disorders. Specifically, we suggest that aberrant steroid hormone-dependent regulation of neuronal calcium influx via extracellular matrix proteins and membrane receptors involved in responding to the cell's microenvironment might be important. Testing of this hypothesis might identify novel therapeutic targets and predictive biomarkers.