Tissue remodelling is an adaptive physiological event initiated by physical and/or hormonal stimuli and characterised by extracellular matrix modifications, inflammation, cellular hypertrophy, proliferation and/or apoptosis. Although its initial effects may be beneficial for the maintenance of organ function, it is evident that sustained remodelling processes can lead to pathological outcomes, such as fibrosis in asthma, and cardiac hypertrophy in heart failure. Our research is focussed upon cardiac hypertrophy and the significant contribution of the molecular pathway, termed 'the triple membrane-passing signalling' paradigm (TMPS), to this phenomenon. Cardiac hypertrophy describes the enlargement, but not proliferation, of cardiomyocytes in response to mechanical or hormonal factors to normalise cardiac output and accompanies other features of cardiac remodelling. As a major independent risk factor for heart failure, it is imperative that the molecular mechanisms that govern this phenotype are determined to identify possible therapeutic targets. This review will focus on the importance of matrix metalloproteases and epidermal growth factor receptors in the TMPS pathway and their potential as pharmacological targets for heart failure therapy. The evidence provided may have implications for pathological tissue remodelling in other organs.