The past several decades have witnessed dramatic changes in the regulatory environment involving the use of animals in research and education. A cursory review of citations using the keywords “animal model or animal models” in PubMed ( http://www.ncbi.nlm.nih.gov/pubmed ) indicates a steady increase in manuscripts involving the use of animals (Figure 7.1). As research findings enhanced collective knowledge and experimental techniques and goals became more sophisticated, scientists demanded greater control of experimental variables. Concerns about variability inherent to animal models, such as housing environment, disease status, procedure-related pain and distress, nutritional stabilization, and sanitation practices, dictated adaptation of recognized standards (Box 7.1). As science continues to globalize, reproducibility and comparability provided by the application of accepted standards become increasingly important.The use of animals for research and teaching has consistently polarized public opinion, and governments have recognized a need for regulations to address the ethical responsibility for acknowledging the needs of the animals used for societal purposes (Schwindaman 1999). Regulations therefore provide a means of reassuring the public that animal use is limited to situations of strict necessity and conforms to their demands for providing species-appropriate daily care, reducing avoidable pain and distress, eliminating unnecessary duplication, and preventing illegal activities, such as animal theft.Therefore, an animal compliance program is simply an oversight system designed to address two fundamental objectives: conformity to established standards as dictated by scientific rigor and assurance of humane animal treatment as demanded by the public (Box 7.2).Those with management responsibilities for animal care and use programs play an important role in ensuring regulatory compliance and in serving as a primary conduit of communication between the animal users and regulatory authorities. Thus, it behooves the manager to develop a keen awareness and understanding of regulatory oversight and the responsibilities of various institutional and external entities involved, and a basic understanding of pertinent laws, regulations, principles, guidelines, and policies at local, state, national, and international levels. This is no small feat; regulatory complexities have been compared with Russian matryoshka dolls with seemingly unending layers of intricacy (Bayne and Garnett 2008). Knowing where to seek additional information is often the most crucial step. The goal of this chapter is to introduce concepts concerning animal program compliance, describe the entities that are commonly involved, and provide a brief summary of pertinent sources of guidance.The reader is strongly encouraged to review the source documents for regulations and guidelines that impact their program directly. No summary can provide adequate detail for the issues raised and discussed in these documents. The intent of the remainder of the chapter is to provide an introduction to the extant regulations and guidance documents around the globe and to identify common themes. Note that AAALAC International maintains an impressive collection of links to U.S. and international regulations (AAALAC 2016c).An introduction to regulations and guiding documents would be remiss without a brief discussion of Russell and Burch’s The Principles of Humane Experimental Technique (1959). This historic text is divided into two parts. Part One, “The Scope of Humane Technique,” describes concepts of inhumanity and underlying themes of removing inhumanity. Part Two, “The Progress of Humane Technique,” introduced what has since been referred to as the three Rs: replacement, reduction, and refinement. Numerous works describe and expand the basic maxims of the three Rs (e.g., Goldberg et al. 1996; Guhad 2005; Bronstad and Berg 2011; Curzer et al. 2013) and encourage their implementation in theory (e.g., Van Zutphen and Van Der Valk 2001; Lloyd et al. 2008; Jennings et al. 2010; Slob 2014; Bratcher and Reinhard 2015; Kramer and Font 2015) and in practice (e.g., Agelan et al. 2008; Kim et al. 2012; Michelini et al. 2014; Lilley et al. 2015), or reflect their influence (e.g., Carlsson et al. 2004; Fenwick et al. 2009; Bayne 2011; Tornqvist et al. 2014).Briefly, replacement strategies include the use of tissue culture, microorganisms, and other models in lieu of live animals. Appropriate study design and analysis of sources of variation address the reduction in numbers of animals required. Refinement may take many paths, but involves consideration of alternatives to potentially painful procedures and other means of minimizing animal distress. The vast majority of, if not all, regulations, guidelines, and other references to animal use in research, teaching, and testing refer to the fundamental concepts of the three Rs, which have been cited as the primary benchmarks for ensuring public confidence and avoiding unnecessary pain and distress (ILAR 2008).