Global biodiversity priority setting underpins the strategic allocation of conservation funds. In identifying the first comprehensive set of global priority areas for mammals, Ceballos et al. [Ceballos G, Ehrlich PR, Soberón J, Salazar I, Fay JP (2005) Science 309:603–607] found much potential for conflict between conservation and agricultural human activity. This is not surprising because, like other global priority-setting approaches, they set priorities without socioeconomic objectives. Here we present a priority-setting framework that seeks to minimize the conflicts and opportunity costs of meeting conservation goals. We use it to derive a new set of priority areas for investment in mammal conservation based on ( i ) agricultural opportunity cost and biodiversity importance, ( ii ) current levels of international funding, and ( iii ) degree of threat. Our approach achieves the same biodiversity outcomes as Ceballos et al.' s while reducing the opportunity costs and conflicts with agricultural human activity by up to 50%. We uncover shortfalls in the allocation of conservation funds in many threatened priority areas, highlighting a global conservation challenge.