Control is a key ingredient of scientific experimentation; arguably, an uncontrolled intervention or manipulation is not even a genuine experiment. Experiments in the life sciences, however, are notoriously difficult to control due to the complexity and variability of living things. This Element discusses general features of controlled experimentation, epistemic and practical aspects, and historical perspectives. It argues that controlled experimentation has a material-technical and a conceptual side. It shifts the focus from control experiments, comparisons with a control, to the broader issue of controlling for background factors as the epistemologically fundamental issue in experimentation. To understand the nature of controlled experimentation, one needs to consider the making – the design phase – of controlled experiments, particularly the conceptualization and treatment of background factors. The making of controlled experiments is at the same time constitutive for the knowledge that can be gained in the experiment, contingent on a research situation, and historically shaped.