This article outlines a pathway to develop the business case for One Health. It describes the origin and development of One Health and then identifies five potential areas where One Health can add value and reduce costs. These are: (1) sharing health resources between the medical and veterinary sectors; (2) controlling zoonoses in animal reservoirs; (3) early detection and response to emerging diseases; (4) prevention of pandemics; and (5) generating insights and adding value to health research and development. Examples are given for each category along with preliminary estimates of the potential savings from adopting the One Health approach. The literature reviewed suggests that one dollar invested in One Health can generate five dollars worth of benefits and a global investment of US$ 25 billion over 10 years could generate benefits worth at least US$125bn. Conservation implications: the time has come to make the bigger case for massive investment in One Health in order to transform the management of neglected and emerging zoonoses and to save the lives of millions of people and hundreds of millions of animals whose production supports and nourishes billions of impoverished people per annum.