Chronic lymphocytic leukaemia (CLL), the most common adult leukaemia in Western societies, is more prevalent in the aging population; the average age at the time of diagnosis is ~70 years old. CLL is characterized by accumulation of mature CD5+ B-cells, primarily as a consequence of impaired apoptosis. Patients with CLL can have indolent disease with minimal clinical manifestations or an aggressive form characterized by high mortality. Prolonged elevation of the second messenger cyclic AMP (cAMP) promotes apoptosis in lymphoid cells, including CLL cells (Zhang et al., 2008). Since the level of cAMP and activity of protein kinase A (PKA) are lower in CLL-cells than in normal B-cells, these data suggest a disease-related defect in cAMP formation, degradation or both in the disease (Zhang et al., 2008). The intracellular level and duration of cAMP is governed by its formation by adenylyl cyclases (ACs), which are primarily regulated by G protein-coupled receptor (GPCR) agonists and degradation by cyclic nucleotide phosphodiesterases (PDEs). The actions of cAMP are largely mediated by PKA and exchange protein directly activated by cAMP (Epac). Compartmentalization of components of cAMP signalling, by bringing cAMP close to specific targets, is also important in shaping functional responses. We hypothesised that analysis of components that mediate cAMP accumulation and signalling in CLL-cells (using peripheral blood mononuclear cells and B-cells isolated from normal- and CLL-patients, together with real-time PCR, immunoblotting and Immunofluorescence) and investigating the mechanisms that contribute to cAMP-promoted apoptosis (using FACS and annexin 5 staining) (methods in Zhang et al., 2008) would highlight ways to selectively increase cAMP and apoptosis in the CLL-cells relative to normal B-cells. This “cAMP-pathway approach” revealed signalling components involved in the progression of the disease and identified GPCR agonists/antagonists, AC isoform activators (e.g., of AC7), PDE inhibitors (e.g., of PDE7B), activators or inhibitors of downstream mediators (PKA and Epac, respectively) and regulators of subcellular microdomains (caveolin-1), which might be utilized for the treatment of CLL. These data provide insight into the pathophysiology and progression of CLL and identify novel drug targets for CLL. Our findings suggest the diagnostic and therapeutic potential of a pathway analysis of the expression and localisation of mediators of cAMP signalling in human disease.