It has been more than two decades since the formulation of the so‐called ‘trade‐off’ hypothesis as an alternative to the then commonly accepted idea that parasites should always evolve towards avirulence (the ‘avirulence hypothesis’). The trade‐off hypothesis states that virulence is an unavoidable consequence of parasite transmission; however, since the 1990s, this hypothesis has been increasingly challenged. We discuss the history of the study of virulence evolution and the development of theories towards the trade‐off hypothesis in order to illustrate the context of the debate. We investigate the arguments raised against the trade‐off hypothesis and argue that trade‐offs exist, but may not be of the simple form that is usually assumed, involving other mechanisms (and life‐history traits) than those originally considered. Many processes such as pathogen adaptation to within‐host competition, interactions with the immune system and shifting transmission routes, will all be interrelated making sweeping evolutionary predictions harder to obtain. We argue that this is the heart of the current debate in the field and while species‐specific models may be better predictive tools, the trade‐off hypothesis and its basic extensions are necessary to assess the qualitative impacts of virulence management strategies.

HIV Virulence: A major focus of research on HIV is on host responses to infection—understandably, because the virus targets the immune system and because of the interest in vaccine development. In reviewing what little research has been done on viral virulence determinants, Fraser et al. ( 10.1126/science.1243727 ) present evolutionary explanations for some of the poorly understood phenomena that mark HIV infection, including long-term survivorship, latency, rapid within-host evolution, and inheritability of between-host virulence.

Until quite recently and since the late 19th century, medical microbiology has been based on the assumption that some micro-organisms are pathogens and others are not. This binary view is now strongly criticised and is even becoming untenable. We first provide a historical overview of the changing nature of host-parasite interactions, in which we argue that large-scale sequencing not only shows that identifying the roots of pathogenesis is much more complicated than previously thought, but also forces us to reconsider what a pathogen is. To address the challenge of defining a pathogen in post-genomic science, we present and discuss recent results that embrace the microbial genetic diversity (both within- and between-host) and underline the relevance of microbial ecology and evolution. By analysing and extending earlier work on the concept of pathogen, we propose pathogenicity (or virulence) should be viewed as a dynamical feature of an interaction between a host and microbes.