This chapter addresses the fundamental nursing role and responsibility of preventing the risk of infection in all healthcare settings. Every nurse should possess the knowledge and skills to assess the risk of infection, to select and implement evidence-based strategies to prevention infection, and to review the effectiveness of these to inform any necessary changes in care. Healthcare-associated infection (HCAI) is the term used to describe an infection that arises as a result of some exposure to healthcare. Unlike the more traditional terms ‘hospital-acquired’ or ‘nosocomial’ infection, this updated term encompasses the range of settings in which healthcare is delivered and from which infections may arise. In recent years, much of the attention on HCAIs has focused on methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile (C. difficile), both of which are closely monitored in acute hospitals and in England as part of a programme of mandatory surveillance (National Audit Office, 2009). It is important to recognize that HCAIs are caused by a wide variety of microorganisms, for example Escherichia coli (E. coli), which require equal attention in clinical practice. Because the principles of infection prevention are applicable to all causes of HCAIs, this chapter focuses on these underpinning principles rather than on specific microorganisms of concern. As a nurse, you have a fundamental responsibility for minimizing the risk of infection in all healthcare settings and in the patient’s own home by understanding and applying these principles in practice. HCAI is a significant problem in all healthcare settings, although much more is known about its prevalence and incidence in hospitals than in other healthcare environments. Prevalence of HCAI is the total number of cases that occur either at a particular time (point prevalence) or over a defined period of time (period prevalence). The UK prevalence surveys, conducted in 2006, estimated that, at any one time, approximately one in eight hospital inpatients has a HCAI (Smyth et al., 2008; Reilly et al., 2008). This figure is comparable with data from inpatient populations in other countries, with reported rates ranging between 3.5% and 9.5% (e.g. European Centre for Disease Prevention and Control, 2008; Gravel et al., 2007; Wu et al., 2005).