Selective membrane fusion underlies subcellular compartmentation, cell growth, neurotransmission and hormone secretion. Its fundamental mechanisms are conserved among organelles, tissues and organisms. As befits a conserved process, reductionism led to its study in microorganisms. Homotypic fusion of the vacuole of Saccharomyces cerevisiae is particularly accessible to study as vacuoles are readily visualized, there is a rapid and quantitative in vitro assay of vacuole fusion, and the genetics and genomics of this organism and of vacuole fusion are highly advanced. Recent progress is reviewed in the context of general questions in the membrane fusion field.