Poly(alkylcyanoacrylate) (PACA) nanoparticles were first developed 25 years ago taking advantage of the in vivo degradation potential of the polymer and of its good acceptance by living tissues. Since then, various PACA nanoparticles were designed including nanospheres, oil-containing and water-containing nanocapsules. This made possible the in vivo delivery of many types of drugs including those presenting serious challenging delivery problems. PACA nanoparticles were proven to improve treatments of severe diseases like cancer, infections and metabolic disease. For instance, they can transport drugs across barriers allowing delivery of therapeutic doses in difficult tissues to reach including in the brain or in multidrug resistant cells. This review gives an update on the more recent developments and achievements on design aspects of PACA nanoparticles as delivery systems for various drugs to be administered in vivo by different routes of administration.