The relationship among microbes, animals, and humans often manifests as zoonotic, anthropo-zoonotic, or sylvatic infections. Infections transmitted from animals to humans are considered zoonotic and often cause outbreaks of diseases, epidemics, or even pandemics. The battle for survival between microbes and mammalian species has been occurring throughout all documented human history. The control, de-escalation, or deceleration of the spread of these diseases often hinges upon the detection of infectious agents. The diagnostic tests to detect and monitor infectious agents have evolved throughout human biomedical history. Infectious disease diagnosis in the past decades has improved by combining physical examination, microbiology, immunology, and molecular tests. This chapter highlights the characteristics of diseases by their clinical presentation, laboratory tests, use of multi-omics, and other attributes of diagnostics.