Emerging infectious diseases and epidemics are often seen at mission health institutions. Work at such Christian institutions seeks to practice holistic medicine, and the core priorities included dedicated clinical care combined with community responsibility. This paper describes some unusual, and some more common epidemics that occurred at three mission hospitals in southern Ethiopia during the last 60 to 70 years. The hospitals covered vast areas and large populations, mostly from poor subsistence farming communities. With great topographical and climatic variations, the catchment areas include multiple climate zones that cause substantial variations in ecology and vegetation, and thus also in disease patterns. Our review is based on personal notes, hospital records, and previous scientific publications. We observed epidemics such as cholera and other diarrheal diseases, relapsing fever, meningitis, gonococcal conjunctivitis, the emerging of HIV and Helicobacter infections, and parasitic infections such as malaria and visceral leishmaniasis. Hospitals should ideally have collaborated with local and national health authorities to combat such events. Unfortunately, that was not always possible because of wars, political unrest or lack of capacity. Sometimes these hospitals did not have sufficient laboratory infrastructure to diagnose infections such as arboviral diseases. More emphasis should have been on enabling the hospitals to both diagnose and control epidemics.