The induction of specific immune responses requires intimate physical interactions between antigen presenting cells (APC) and CD4 Th-cells. Ligation of the clonally distributed receptor for antigen (TCR) by microbial peptides bound to MHC molecules on the surface of APC provides a signal to the T-cell. The functional outcome of this signal, however, is determined by constimulatory or accessory signals provided by specialised APC surface macromolecules binding to accessory receptors on the T-cell. In this way TCR ligation can result in clonal expansion, anergy or apoptosis depending on the nature of simultaneous constimulatory signalling. In addition to, and as a consequence of, these macromolecular interaction, transient covalent chemical events also occur between ligands on APC and T-cell. These take the form of Schiff base formation between constitutive amines and carbonyl groups. Schiff base formation on specialised T-cell surface amines provides a constimulatory signal to the T-cell involving activation of Na⁺  and K⁺ transport and convergence with the TRC-signalling cascade at the level of the mitogen activated protein kinase ERK2. Constimulation of this kind favours Th1- type cytokine production, and cell-mediated effector mechanisms. Small Schiff base-forming molecules can mimic the effects of the constitutive cell-surface ligands and provide a costimulatory signal to CD4 Th-cells which substantially enhances immune responses. One such molecule, the substituted benzaldehyde tucaresol, has been developed as an orally bioavailable, systemically active immunopotentiatory drug. Tucaresol has been shown to be therapeutically effective in murine models of viral infection and tumour growth and is undergoing phase I/II clinical trials in chronic viral infection and malignant melanoma.