Combinatorial synthesis was originally conceived and pitched to solve one of the most vexing problems in high-throughput screening: library generation. Using split-and-pool methods, million-member compound collections could be accessed quickly and cheaply, but early combinatorial library chemotype mainstays (peptides) were not drug-like, adapting the libraries to robotic automation proved problematic, and screening hit deconvolution invariably lacked the necessary statistical power. DNA-encoded library (DEL) technology has resurrected combinatorial chemistry by enabling the construction of vast compound collections (> 107) of drug-like compounds that are evaluated en masse by affinity selection and deconvoluted with high statistical power via next-generation DNA sequencing (NGS). My laboratory has expanded on this powerful lead generation concept, engineering highly integrated microfluidic droplet-based circuits and bead-based DEL synthesis strategies that enable the direct functional interrogation of DELs. The circuits load library beads into picoliter-scale activity assay droplets, photochemically cleave the library member to dose the droplet, incubate the droplets, detect each droplet’s assay result at high speed, and sort droplets that signal the presence of a bioactive compound for subsequent NGS. I will discuss the design, synthesis, and characterization of 3 drug-like bead DELs ranging in diversity (10–100k members) and the microfluidic functional screening of these libraries using classic enzyme/substrate assays (HIV protease, autotaxin). I will also discuss a new in-droplet fluorescence polarization (FP) detection system for microfluidic DEL screening when a fluorometric activity assay is unavailable. Finally, as an example of a target that would be difficult to prosecute using convention DEL technology, I will also present library screens of a complex metabolism — bacterial reporter gene in vitro translation — and several families of bacterial translation inhibitors that were discovered in the screen. This bead-based DNA-encoded library and accompanying functional screening technology now raises the possibility of conducting DEL screens against a variety of complex, metabolizing systems, such as lysates, cellular targets, and tissues.