Nanogels have been identified as outstanding nanocarrier candidates for drug delivery due to their desirable physiochemical properties and versatile applicability for diverse therapeutic molecules and imaging probes. One of the main challenges that hinder the clinical translation of nanogels is the low efficiency of drug delivery to the target sites because of the complex biological barriers during the in vivo journey. The purpose of this review is to examine and summarize the recent advances on the rational design and structural modulation of nanogels to overcome the barriers and challenges on the way to the site of action following various dosing modes. In particular, the functional moieties or domains have been incorporated in the nanogels, allowing them to spontaneously regulate their structure and physiochemical properties to cross one or more of the multifaceted barriers. In addition, the future perspectives are presented with regards to opportunities and challenges for the precise and efficient therapeutic use of nanogel formulations.