Biological membrane fusion is driven by different types of molecular fusion machines. Most of these proteins are membrane-anchored by single transmembrane domains. SNARE proteins are essential for intracellular membrane fusion along the secretory and endocytic pathway, while various viral fusogens mediate infection of eukaryotic cells by enveloped viruses. Although both types of fusion proteins are evolutionarily quite distant from each other, they do share a number of structural and functional features. Their transmembrane domains are now known to be critical for the fusion reaction. We discuss at which stages they might contribute to bilayer mixing.