Infectious diseases pose some of the most significant health threats we face today, whether because of antimicrobial resistance, the emergence of new zoonotic infections, changing climate or other challenges in our globalised world. At the same time, our growing understanding of microbial-host relationships is offering us radically new ways to respond to these threats and even to reduce the burden of non-communicable disease. These extraordinary developments are the outcomes both of blue sky research and of research focussed on solving particular problems, identified by researchers themselves or called for by a funding agency. As we plan how NHMRC and the Medical Research Future Fund should collectively support Australia’s health and medical research effort, we need to consider the balance of investment between exploration and problem-solving, between disease prevention and treatment, and between research on the urgent issues of today and the foreseeable threats of the future.