The insulin-like growth factor 1 (IGF1)–phosphoinositide 3-kinase (PI3-K) pathway is a critical regulator of cell and organ growth. 2. In the heart, the IGF1–PI3-K pathway induces physiological heart growth with preserved or enhanced cardiac function. 3. The present review specifically discusses the role of the IGF1–PI3-K pathway in the setting of heart disease. 4. Genetic mouse models have highlighted the beneficial effects of the IGF1–PI3-K pathway in the heart in a setting of disease. These include maintenance of contractile function, antifibrotic and anti-apoptotic actions, inhibition of signalling transducers activated in disease settings and regeneration.