This chapter is dedicated to explaining the principle of PEGylation in the solubilization of nanocarriers for pharmaceutical and biomedical applications, in addition to the enhancement of the propensity of these carriers to solubilize drugs. The chapter introduces the general rationale for nanocarrier PEGylation with a specific focus on the topic of solubilization in addition to the solubility characteristics of PEG. PEGylated small molecular weight drugs and proteins are briefly introduced to emphasize the stages of pharmaceutical solubilization by PEGylation. Furthermore, protein PEGylation as a means to solubilize enzymes and proteins for facilitated nanoparticle production is highlighted. Proposed mechanisms and factors affecting the drug solubilization propensity of PEGylated nanocarriers are also explored. Illustrative examples and reviewed applications are included wherever appropriate.