Monkeypox virus (MPXV), which causes disease in humans, has for many years been restricted to the African continent, with only a handful of sporadic cases in other parts of the world. However, unprecedented outbreaks of monkeypox in non-endemic regions have recently taken the world by surprise. In less than 4 months, the number of detected MPXV infections has soared to more than 48,000 cases, recording a total of 13 deaths. In this Review, we discuss the clinical, epidemiological and immunological features of MPXV infections. We also highlight important research questions and new opportunities to tackle the ongoing monkeypox outbreak.