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Organizational change is a key mechanism to ensure the sustainability of healthcare systems. However, healthcare organizations are persistently difficult to change, and literature is riddled with examples of failed change endeavors. In this chapter, we attempt to unravel the underlying causes for failed organizational change. We distinguish three types of change with different levels of depth that require different change approaches. Transformations are the deepest forms of change where beliefs and principles need to be modified to successfully influence routines. Renewals are deep forms of change where principles need to be modified to successfully influence routines. Improvements are shallow forms of change where only modifications at the level of routines are needed. Using deoxyribonucleic acid (DNA) as our metaphor, we propose a theory of “organizational DNA” to understand organizations and these three types of organizational changes. We posit that organizations are made up of a double helix consisting of a so-called “social string,” which contains the “soft” interaction or communication among the organization's members, and a so-called “technical string,” which contains “hard” organizational aspects such as structure and technology. Ladders of organizational nucleotides (i.e., Routines, Principles, and Beliefs) connect this double helix in various combinations. Together, the double helix and accompanying nucleotides make up the DNA of an organization. Without knowledge of the architecture of organizational DNA and whether a change addresses beliefs, principles, and/or routines, we believe that organizational change is constrained and based on luck rather than change management expertise. Following this metaphor, we show that organizational change fails when it attempts to change one part of the DNA (e.g., routines) in a way that renders it incompatible with the connecting components (e.g., principles and beliefs). We discuss how the theory can be applied in practice using an exemplar case.