The nonviral delivery of exogenous nucleic acids (NA) into cells for therapeutic purposes has rapidly matured into tangible clinical impact. Synthetic polymers are particularly attractive vectors for NA delivery due to their relatively inexpensive production compared to viral alternatives and their highly tailorable chemical properties; indeed, many preclinical investigations have revealed the primary biological barriers to nonviral NA delivery by systematically varying polymeric material properties. This review focuses on applications of pH-sensitive chemistries that enable polymeric vectors to serially address multiple biological barriers to NA delivery. In particular, we focus on recent innovations with in vivo evaluation that dynamically enable colloidal stability, cellular uptake, endosomal escape, and nucleic acid release. We conclude with a summary of successes to date and projected areas for impactful future research.