Target-specific therapeutic modalities solve shortcomings associated with traditional medication administration and therapy. The success of liposomes, polymeric nanoparticles (NPs), dendrimers, micelles, protein-drug conjugates, and other nanoplatforms in improving the pharmacokinetics and biodistribution of the therapeutic after systemic administration has led to promising results in clinical settings and market traction. NPs have been the gold standard for medication administration for millennia; however, this conventional method still faces problems with drug solubility, sustained payload release, and getting the necessary treatment to the targeted sickness site. NPs-mediated drug administration and targeting are further improved by encasing nanoformulations in a stealth coating made of hydrophilic polymers authorized by the FDA, such as PEG, chitosan, polyacrylamides, etc. The NPs are protected by this surface layer against opsonization, immune system recognition, and aggregation. The benefits and requirements for the PEGylation of NPs are discussed in this chapter. Here, the focus is on NPs as a means of drug administration and how the PEGylation of NPs enhances their therapeutic utility. Several PEGylated NPs that have demonstrated promising outcomes for both systemic and nonsystemic drug delivery have also been highlighted.