Interest in CRISPR/Cas9 remains high level as new applications of the revolutionary gene-editing tool continue to emerge. While key structural and biochemical findings have illuminated major steps in the enzymatic mechanism of Cas9, several important details remain unidentified or poorly characterized that may contribute to known functional limitations. Here we describe the foundation of research that has led to a fundamental understanding of Cas9 and address mechanistic uncertainties that restrict continued development of this gene-editing platform, including specificity for the protospacer adjacent motif, propensity for off-target binding and cleavage, as well as interactions with cellular components during gene editing. Discussion of these topics and considerations should inspire future research to hone this remarkable technology and advance CRISPR/Cas9 to new heights.