After years of confusion about apparently distinct clinical disease symptoms, the term IgG4-related disease (IgG4-RD) has been coined in 2001, uniting these fibroinflammatory clinical entities with a tendency for tumorous enlargement and tissue fibrosis. Over the past two decades, experimental and clinical studies could make astounding progress in the understanding of this elusive disease. By now, we have a reasonable idea of the pathophysiological mechanisms, which opens up new avenues for therapeutic approaches. It seems like a dense lymphoplasmacytic cell infiltrate, consisting of B‑cells, IgG4+ plasma cells, follicular T‑helper cells, CD4+ cytotoxic T‑cells and M2 macrophages induces a smoldering inflammatory reaction with a fibrogenic cytokine milieu. This stimulates fibroblasts to secrete extracellular matrix components, leading to the histopathologically characteristic storiform fibrosis and obliterative phlebitis. Macroscopically, this reaction results in diffuse organ swelling and tumorous lesions. The macroscopic and histological differentiation from conditions mimicking IgG4-RD can be challenging. This is especially true for granulomatous diseases, such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The situation is further complicated by the fact that ANCAs can be positive in IgG4-RD and, vice versa IgG4 antibodies can be elevated in numerous differential diagnoses, such as infections, AAV, sarcoidosis, and malignancies. This article provides an overview of the multifaceted clinical condition of IgG4-RD with respect to the pathophysiology, diagnostic steps and treatment. Furthermore, an overview of the differential diagnoses is discussed especially with respect to granulomatous diseases.