<p>About 15–20% of women experience postnatal depression and may seek advice about medication use whilst breastfeeding. Venlafaxine is a potent and selective neuronal serotonin-norepinephrine reuptake inhibitor indicated for treating major depressive disorders. The drug is mainly metabolised by cytochrome P450 2D6 (CYP2D6) to its active metabolite O-desmethylvenlafaxine (ODV), with small contributions from CYP2C9 and CYP2C19. Subsequently, the formed ODV undergoes CYP3A4- and UGT-mediated metabolism and renal excretion. A physiologically based pharmacokinetic (PBPK) model describing the disposition of both venlafaxine and ODV was developed. Consistent with observed data, simulations showed that exposure of the combined active moieties (venlafaxine plus ODV) was similar for both CYP2D6 extensive (EM) and poor metaboliser (PM) subjects. Clinical lactation data for venlafaxine were available from several studies but CYP genotypes were not recorded. Interestingly, based on simulated exposures in breast milk, the estimated average relative infant daily dose (RIDD) ranged from 3.8% for all EMs to 7.6% for all PMs of CYP2D6, CYP2C9 and CYP2C19. Furthermore, simulations in breastfed infants indicated that both CYP polymorphisms and enzyme ontogenies contribute to the significant variability that is observed clinically but the combined exposures of venlafaxine and ODV remain below the thresholds that have been reported for adverse events in adults and children. The data generated here add to the existing knowledge base and can help clinicians and their patients make a more informed decision on the use of venlafaxine during breastfeeding.</p>