Organic synthesis problems require the solver to integrate knowledge and skills from many parts of their courses. Without a well-defined, systematic method for approaching them, even the strongest students can experience difficulties. Our research goal was to identify the most successful problem-solving strategies and develop associated teaching models and learning activities. Specifically we asked: (1) What problem-solving strategies do undergraduate students use when solving synthesis-type problems? Are these strategies used correctly/as intended? (2) What strategies have the highest association with successful answers? (3) What relationships exist between these strategies? We analyzed more than 700 responses to synthesis problems from the final exams of undergraduate organic chemistry courses at a large, research-intensive institution. We analyzed the data using an open-coding system and a theoretical framework based on meaningful learning and representational systems in problem-solving. Our analysis found that successful answers demonstrated six key strategies: (1) identified newly formed bonds in the target molecule, (2) identified atoms added to the starting molecule to form the target, (3) identified key regiochemical relationships, (4) mapped the atoms of the starting material onto the target, (5) used a partial or complete retrosynthetic analysis, and (6) drew reaction mechanisms. The vast majority of successful answers demonstrated the use of multiple strategies in concert. This higher degree of success is logical in the context of meaningful learning and of representational systems in problem-solving. These strategies were often absent from unsuccessful answers, possibly because students did not know these strategies, did not believe them to be useful, or did not write them down. For teaching, our results suggest that students should be taught, encouraged, and given opportunities to use multiple key strategies; sample problems are included herein.