In the 70s, the discovery of a constant loss of acetylcholine (Ach) in the brains of people suffering from dementia led to the development, in order to improve cognitive functions, of drugs that increased Ach levels. The possibility that loss of a given neurotransmitter might be associated with the onset of a specific neurological syndrome led to suggestions that, as had already been found in Parkinson's disease, replacement therapy might drastically improve the course of the syndrome. We are now aware of the limits of this therapeutic approach. In this review, we analyse potential factors contributing to the partial failure of Ach replacement therapy, contrasting common beliefs regarding the Ach synapse with the difficulties in restoring its activity through replacement drugs. Considering the search for alternative strategies, in the second part of the review, we overview progress of research into pyrimidine compounds, now emerging as a new modulatory system acting through specific pyrimidino-receptors involved in various steps of cell signalling. Pyrimidine nucleosides might be useful in the chronic treatment of cognitive deficits resulting from vascular dementia.