The complexity of the Notch signalling pathway has impeded progress in understanding its precise role in differentiation processes of the mature peripheral immune system. Nevertheless, both B and T lymphocyte responses are undoubtedly influenced by Notch ligation, and defining the mechanisms by which this is achieved remains a challenge. How the innate-adaptive interface and interactions between lymphocytes can be affected, together with the potential of this pathway for therapeutic intervention remain important and stimulating issues.