While the fragment‐based drug design approach continues to gain importance, gaps in the tools and methods available in the identification and accurate utilization of protein subpockets have limited the scope. The importance of these features of small molecule–protein recognition is highlighted with several examples. A generalized solution for the identification of subpockets and corresponding chemical fragments remains elusive, but there are numerous advancements in methods that can be used in combination to address subpockets. Finally, additional examples of approaches that consider the relative importance of small‐molecule co‐dependence of protein conformations are highlighted to emphasize an increased significance of subpockets, especially at protein interfaces.