Diagnostics is a crucial tool in health care's endeavours to help people, and tremendous progress has been made in the field. Nonetheless, there are a wide range of uncertainties involved in all aspects of diagnostics -uncertainties that are important for scientific improvement, for quality of care, for practicing medicine, for informing patients, and for health policy making. In this chapter we analyse a wide range of uncertainties presenting in the various steps of diagnostic imaging. For each step we describe the main concern and suggest measures to reduce and handle the various kinds of uncertainty. Overall, we provide 9 specific measures to reduce uncertainty in the diagnostic process. Moreover, we analyse ethical issues related to the various types of uncertainty presenting at each step and end the chapter with five specific questions framed to raise the awareness of uncertainty in diagnostic imaging, as well as to reduce and to handle it. Thereby we hope that this chapter will provide practical measures to acknowledge and address diagnostic uncertainty.