Solving serologic problems and teaching others how to solve these problems can present a challenge to even the most experienced technologists. Those so-called expert immunohematologic problem-solvers may never have had the opportunity to step back and evaluate how they approach a problem and the steps they take to resolve it. The first chapter reviews the problem-solving process, including in what manner an individual approaches any problem. In the remaining chapters, the problem-solving model is applied to many types of serologic problems and is emphasized through case studies.