Negative pressure wound therapy is used often in the management of surgical incisions, chronic wounds and subacute lesions, and there are numerous publications discussing its clinical application and outcomes. However, whilst clinical use and associated literature have expanded since these systems became commercially available in the 90s, important research and discussion around the mode of action have waned, leading to a deficit in the understanding of how this important therapy influences healing. Further, much research and many publications are predominantly reflective, discussing early theorem, some of which have been proven incorrect, or at least not fully resolved leading to misunderstandings as to how the therapy works, thus potentially denying the clinician the opportunity to optimise use towards improved clinical and economic outcomes. In this narrative review, we discuss established beliefs and challenges to same where appropriate and introduce important new research that addresses the manner in which mechanical strain energy (i.e., deformations) is transferred to tissue and how this influences biological response and healing. In addition, we assess and discuss the effect of different negative pressure dressing formats, how they influence the mode of action and how this understanding can lead to more efficient and effective use and clinical economic outcomes.