With over 2 million cancer cases and over 600,000 cancer-associated deaths predicted in the U.S. for 2022, this life-debilitating disease continuously impacts the lives of people across the nation every day. Therapeutic treatment options for cancer have historically involved chemotherapies to eradicate tumors with cytotoxic mechanisms which can negatively affect the efficacy versus toxicity ratio of treatment. With a need for more directed and therapeutically active options, targeted small-molecule inhibitors and immunotherapies have since emerged to mitigate treatment-associated toxicities. However, aggressive tumors can employ a wide range of defense mechanisms to evade monotherapy treatment altogether, resulting in the recurrence of therapeutically resistant tumors. Therefore, many clinical routines have included combination therapy in which anticancer agents are combined to provide a synergistic attack on tumors. Even with this approach, maximizing the efficacy of cancer treatment is contingent upon the dose of drug that reaches the site of the tumor, so often therapy is administered at the site of a tumor via localized delivery platforms. Commonly used platforms for localized drug delivery include polymeric wafers, nanofibrous scaffolds, and hydrogels where drug combinations can be loaded and delivered synchronously. Attaining synergistic activity from these localized systems is dependent on proper material selection and fabrication methods. Herein, we describe these important considerations for enhancing the efficacy of cancer combination therapy through biodegradable, localized delivery systems.