Drug molecules often display little affinity for nonhealthy tissues and/or cells, leading to inefficiency, and high incidence of severe side effects. To face the problem, numerous strategies have been postulated, i.e., chemical modifications to the drug molecule, and proper engineering of drug nanocarriers. In this line, the introduction of poly(D,L-lactide-co-glycolide) nanoparticles in the drug delivery arena has been hypothesized to optimize drug biodistribution and concentration into the targeted site, thus improving the therapeutic effect while reducing the associated drug toxicity. Recent advances in the field have been devoted to the optimization of the in vivo fate and effectiveness of poly(D,L-lactide-co-glycolide)-based drug nanocarriers, i.e., by passive targeting strategies based on the functionalization of the particle surface with special biomolecules, and/or active targeting stratagems thanks to modifications leading to stimuliresponsive nanoparticles. In this chapter, we analyze the current state of the art and future perspectives in the formulation of poly(D,L-lactide-co-glycolide)-based nanomedicines against severe diseases.