The porcine respiratory disease complex describes a clinical condition that often manifests as treatment-resistant respiratory disease of growing to finishing pigs. Its multifactorial etiology includes infectious and non-infectious factors. Besides management and hygiene conditions, particularly viral and bacterial pathogens contribute to the development and course of PRDC. The porcine reproductive and respiratory syndrome virus (PRRSV), porcine circovirus type 2 (PCV2), influenza A virus (IAV) and Mycoplasma (M.) hyopneunoniae are considered as the major pathogens involved in PRDC. The clinical outcome and necropsy findings may differ depending on the involvement of the different pathogens. The complex nature of the PRDC impedes the diagnostic and preventive measures on affected farms. The present review provides insight into the pathomorphology, pathogenesis and inter-pathogen-interactions and aims to support practitioners in implementing purposeful diagnostic and preventive measures.