The story of heart failure (HF) traces a path from the oldest records of human healing practices several millennia ago, winding through various changing models of physiology, sickness and health. It passes through today’s landscape of neurohormonal modulation, device therapy, and assist devices, towards a future of therapies, some in development today, some as-yet unimagined, based on pathophysiological insights yet to come. This review attempts to follow the path and notes the traces left by earlier travellers, as well as the therapeutic improvements made possible by the developments in our understanding of HF that followed from their successes and failures. As we focus on pathophysiology, transplantation and mechanical assist devices will be treated more cursorily. Likewise, as this is a history of the development of modern (sometimes ‘Western’ although more properly ‘global’ or ‘scientific’) medicine, alternative therapies are not discussed in this paper.