A versatile "top-down" method for the fabrication of particles, Particle Replication In Nonwetting Templates (PRINT), is described which affords absolute control over particle size, shape, and composition. This technique is versatile and general enough to fabricate particles with a variety of chemical structures, yet delicate enough to be compatible with sophisticated biological agents. Using PRINT, we have fabricated monodisperse particles of poly(ethylene glycol diacrylate), triacrylate resin, poly(lactic acid), and poly(pyrrole). Monodisperse particle populations, ranging from sub-200 nm nanoparticles to complex micron-scale objects, have been fabricated and harvested. PRINT uses low-surface energy, chemically resistant fluoropolymers as molding materials, which eliminates the formation of a residual interconnecting film between molded objects. Until now, the presence of this film has largely prevented particle fabrication using soft lithography. Importantly, we have demonstrated that PRINT affords the simple, straightforward encapsulation of a variety of important bioactive agents, including proteins, DNA, and small-molecule therapeutics, which indicates that PRINT can be used to fabricate next-generation particulate drug-delivery agents.