The immune system profoundly affects the outcome of every child admitted to paediatric intensive care. Its complexity derives from the need to provide a rapid response to invading pathogens and yet to regulate this response to limit inflammatory damage to host tissues. This is achieved through mucosal immunity, circulating mediators of infection, and diverse cell types of the innate and adaptive immune system. These include phagocytes (neutrophils, monocytes, and dendritic cells), natural killer cells, professional antigen-presenting cells (dendritic cells, macrophages and B cell populations), T cells that orchestrate the adaptive immune response and may also be cytotoxic, and antibody-producing B cells. The definition of sepsis (in adults) as a dysregulated host response to infection, and the recent SARS-CoV-2 pandemic, have emphasised the need for improved understanding of immunomodulation. Tentative steps have been made towards stratifying patients by immune phenotype, but much more needs to be done by intensivists to realise the goal of personalised immunomodulation in sepsis.