The paper presents an ultrahigh-throughput screening platform using drop-based microfluidics, which overcomes the limitations of traditional high-throughput methods and revolutionizes the scale and speed of screening. The platform uses aqueous drops dispersed in oil as picoliter-volume reaction vessels, allowing for screening rates of thousands per second. The authors demonstrate the power of this platform by applying it to directed evolution, identifying new mutants of the enzyme horseradish peroxidase (HRP) with catalytic rates more than 10 times faster than their parent enzyme. The system enables the screening of ~10^10 individual enzyme reactions in only 10 hours, using less than 150 μL of total reagent volume, representing a 1,000-fold increase in speed and a 1-million-fold reduction in cost compared to state-of-the-art robotic screening systems. The platform's ability to handle large libraries and its sensitivity make it particularly useful for directed evolution and other biotechnologies.The paper presents an ultrahigh-throughput screening platform using drop-based microfluidics, which overcomes the limitations of traditional high-throughput methods and revolutionizes the scale and speed of screening. The platform uses aqueous drops dispersed in oil as picoliter-volume reaction vessels, allowing for screening rates of thousands per second. The authors demonstrate the power of this platform by applying it to directed evolution, identifying new mutants of the enzyme horseradish peroxidase (HRP) with catalytic rates more than 10 times faster than their parent enzyme. The system enables the screening of ~10^10 individual enzyme reactions in only 10 hours, using less than 150 μL of total reagent volume, representing a 1,000-fold increase in speed and a 1-million-fold reduction in cost compared to state-of-the-art robotic screening systems. The platform's ability to handle large libraries and its sensitivity make it particularly useful for directed evolution and other biotechnologies.