This chapter broadens the perspective on causes of failures, enabling the deeper analyses of subsequent chapters addressing proximate, distal, and ultimate causes. The rich history of multi-level analysis and modeling is briefly reviewed, citing key contributions by a wide range of research disciplines. Numerous applications of the multi-level framework in a variety of domains, including healthcare delivery, academia, traffic congestion, and air transport are discussed, including the insights gained from use of the framework. An overall methodology for applying this framework is presented and elaborated. The application of this methodology to the line of reasoning throughout this book is summarized.