Membrane fusion is a fundamental biochemical reaction and the final step in all vesicular trafficking events. It is crucial for the transfer of proteins and lipids between different compartments and for exo- and endocytic traffic of signaling molecules and receptors. It leads to the reconstruction of organelles such as the Golgi or the nuclear envelope, which decay into fragments during mitosis. Hence, controlled membrane fusion reactions are indispensible for the compartmental organization of eukaryotic cells; for their communication with the environment via hormones, neurotransmitters, growth factors, and receptors; and for the integration of cells into multicellular organisms. Intracellular pathogenic bacteria, such as Mycobacteria or Salmonellae, have developed means to control fusion reactions in their host cells. They persist in phagosomes whose fusion with lysosomes they actively suppress-a means to ensure survival inside host cells. The past decade has witnessed rapid progress in the elucidation of parts of the molecular machinery involved in these membrane fusion reactions. Whereas some elements of the fusion apparatus are remarkably similar in several compartments, there is an equally striking divergence of others. The purpose of this review is to highlight common features of different fusion reactions and the concepts that emerged from them but also to stress the differences and challenge parts of the current hypotheses. This review covers only the endoplasmic fusion reactions mentioned above, i.e., reactions initiated by contacts of membranes with their cytoplasmic faces. Ectoplasmic fusion events, which depend on an initial contact of the fusion partners via the membrane surfaces exposed to the surrounding medium are not discussed, nor are topics such as the entry of enveloped viruses, formation of syncytia, gamete fusion, or vesicle scission (a fusion reaction that leads to the fission of, e.g., transport vesicles).