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The macroscopic properties of materials exposed to irradiation are determined by radiation damage effects which occur on the nanoscale. These phenomena are complex dynamic processes in which many competing mechanisms contribute to the evolution of the microstructure and thus to its end-state. To explore and understand the behavior of existing materials and to develop new technologies, it is highly advantageous to be able to observe the microstructural effects of irradiation as they occur. Transmission electron microscopy with in situ ion irradiation is ideally suited to this kind of study. This review focuses on some of the important factors in designing this type of experiment including sample preparation and ion beam selection. Also presented are a brief history of the development of this technique and an overview of the instruments in operation today including the latest additions.