One of the major intracellular barriers to non-viral gene delivery is degradation through the endosomal/lysosomal pathway. To overcome this barrier, pH-sensitive polymers that swell in acidic pH and ultimately disrupt the endosome can be designed to escape these compartments. Previously, the Pun lab developed HPMA-oligolysine copolymers that have transfection efficiencies approaching that of polyethylenimine (PEI), the gold standard for transfection. In order to increase the copolymers’ transfection efficiency, oligohistidines were incorporated into the copolymer in both statistical and block architectures to impart pH-sensitivity. Transfection studies with these two copolymers showed that statistical incorporation of oligohistidine increased transfection efficiency, while block incorporation did not increase transfection efficiency. To determine if structure-function differences affected cellular uptake and endosomal buffering, we performed uptake inhibitor and endocytic buffering inhibitor studies. Through these studies, we found that both copolymer geometries preferred non-clathrin coated caveolae uptake pathways, and that they differed in endosomal buffering capabilities. The statistical copolymer showed increased endosomal buffering capacity, which was consistent with the overall higher transfection efficiency of the statistical copolymers over the block copolymers. From these two studies, we are better able to understand the relationship between structure and function in gene delivery using polymers.