The article reviews the roles of SNARE and SM (Sec1/Munc18-like) proteins in intracellular membrane fusion. SNARE proteins, which form α-helical bundles, generate the force required for fusion by pulling two membranes together. SM proteins, shaped like clasps, bind to these SNARE complexes to direct their fusogenic action. The specific combinations of SNARE and SM proteins ensure the specificity of fusion reactions, which are controlled by regulators that integrate the machinery into physiological contexts. The regulation is particularly evident in synaptic exocytosis, where synaptotagmin and complexin cooperate to control the precise timing of neurotransmitter release. The review also discusses the structure and function of SNARE and SM proteins, and the mechanisms by which they work together to drive membrane fusion. The authors suggest a unified view of how SNARE and SM proteins function as the universal fusion machinery, providing insights into the regulation of membrane fusion in various cellular processes and its implications for diseases such as diabetes, immune deficiency, and Parkinson’s disease.The article reviews the roles of SNARE and SM (Sec1/Munc18-like) proteins in intracellular membrane fusion. SNARE proteins, which form α-helical bundles, generate the force required for fusion by pulling two membranes together. SM proteins, shaped like clasps, bind to these SNARE complexes to direct their fusogenic action. The specific combinations of SNARE and SM proteins ensure the specificity of fusion reactions, which are controlled by regulators that integrate the machinery into physiological contexts. The regulation is particularly evident in synaptic exocytosis, where synaptotagmin and complexin cooperate to control the precise timing of neurotransmitter release. The review also discusses the structure and function of SNARE and SM proteins, and the mechanisms by which they work together to drive membrane fusion. The authors suggest a unified view of how SNARE and SM proteins function as the universal fusion machinery, providing insights into the regulation of membrane fusion in various cellular processes and its implications for diseases such as diabetes, immune deficiency, and Parkinson’s disease.