One of the most remarkable aspects of the human body lies in its ability to protect itself from threats and repair damage. The human immune system’s dynamic ability to generate a tremendous variety of molecules and cells capable of recognizing and eliminating foreign invaders is truly awe-inspiring. This sense of wonder sparked scientific and medical curiosity, particularly as people in the eighteenth century, and before, recognized that individuals who survived the ravages of epidemic disease were generally unaffected upon exposure to the same pathogen a second time. Around 1798, Edward Jenner observed that milkmaids who had contracted the relatively mild cowpox exhibited subsequent immunity to the far more severe smallpox. This observation led to the development of the world’s first smallpox vaccine. Vaccination represents one of modern medicine’s greatest triumphs. Alarmingly, over the past two decades of the twenty-first century, growing numbers of people in the industrialized nations have opted to decline some or all vaccinations. As a result, the responsibility for addressing declining vaccination rates has fallen on healthcare workers, who must understand the arguments presented by vaccine skeptics and stay informed about the latest vaccination knowledge. We present five clinical cases focused on vaccine scenarios that highlight common arguments against vaccination for use in the vaccine hesitancy curriculum. The cases in this chapter serve as a rich educational resource for active-learning sessions by providing real-life clinical scenarios and opportunities for rich discussion surrounding the benefits of vaccination.