ETHNOPHARMACOLOGICAL RELEVANCE: The four South African medicinal plants Agapanthus campanulatus (AC), Boophone distica (BD), Mondia whitei (MW) and Xysmalobium undulatum (XU) are used in traditional medicine to treat depression. AIM: To evaluate the effect of ethanolic extracts of the plants in models for depression. MATERIALS AND METHODS: The extracts were screened for affinity for the serotonin transporter (SERT) in the [(3)H]-citalopram-binding assay. The inhibitory potency of the extracts towards the SERT, the noradrenalin transporter (NAT) and the dopamine transporter (DAT) were determined in a functional uptake inhibition assay. Antidepressant-like effects of the extracts were investigated using the tail suspension test (TST) and the forced swim test in both rats (rFST) and mice (mFST). RESULTS: All four plants showed affinity for SERT in the binding assay. AC and BD showed functional inhibition of SERT, NAT and DAT, MW affected SERT while XU showed no effect. BD showed significant effect in the TST and in the mFST/rFST, AC showed significant effect in mFST, MW showed significant effect in the rFST and XU showed significant effect in the mFST. CONCLUSION: In this study we have demonstrated the antidepressant activity of four South African medicinal plants in vitro and in vivo, supporting their rational use in traditional medicine.