We build custom laser microscopes and apply Total Internal Reflection Fluorescence (TIRF) microscopy to follow in real time hundreds of virus particles undergoing various molecular transitions that precede productive cell entry. Statistical analyses of individual-virion data – combined with structure-based mutagenesis and computer simulations that verify experimentally derived models – have led to a detailed molecular description capturing the sequence of events at the virus-target membrane interface that induce fusion of the participating membranes. By answering questions about what is fundamental about the viral fusion mechanism and what available options a virus has to change, it is becoming possible to think a step ahead of the virus to devise novel treatment approaches.