Manic depressive illness (MDI) is a common, severe, chronic and often life-threatening illness. Despite well-established genetic diatheses and extensive research, the biochemical abnormalities underlying the predisposition to, and the pathophysiology of, these disorders remain to be clearly established. Despite formidable obstacles in our attempts to understand the underlying neurobiology of this illness, there is currently considerable excitement about the progress that is being made using novel strategies to identify changes in gene expression that may have therapeutic relevance in the long-term treatment of MDI. In this paper, we describe our recent research endeavours utilizing newer technologies, including a concerted series of mRNA RT–PCR studies, which has led to the identification of novel, hitherto completely unexpected targets for the long-term actions of mood stabilizers – the major cytoprotective protein bcl-2, a human mRNA binding (and stabilizing) protein, AUH, and a Rho kinase. These results add to the growing body of data suggesting that mood stabilizers may bring about some of their long-term benefits by enhancing neuroplasticity and cellular resilience. These results are noteworthy since recent morphometric brain imaging and post-mortem studies have demonstrated that MDI is associated with the atrophy and/or loss of neurons and glia. The development of novel treatments which more directly target molecules involved in critical CNS cell survival and cell death pathways have the potential to enhance neuroplasticity and cellular resilience, and thereby modulate the long-term course and trajectory of these devastating illnesses.