Proof of the Germ theory of disease and acceptance of Koch's postulates in the late 1890's launched the fields of microbial pathogenesis and infectious diseases and provided the conceptual framework that has guided thought and research in these fields. A central tenet that emerged from studies with microbes that fulfilled Koch's postulates was that microbes that caused disease had characteristics that allowed them to do so, with the corollary that microbes that did not cause disease lacked disease-causing determinants. This observation, which held true for many diseases that were known to cause disease in the late 19(th) century, such as toxin-producing and encapsulated bacteria, led to the view that the ability to cause disease rested with microbes and reflected the activity of specific determinants, or virulence factors. With the dawn of the 20(th) century, efforts to neutralize virulence factors were under development and ultimately translated into anti-microbial therapy in the form of antibodies targeted to toxins and polysaccharide capsules. However, the 20(th) century progressed, antibiotics were identified and developed as therapy for infectious diseases while other medical advances, such as specialized surgeries, intensive care units, intravenous catheters, and cytotoxic chemotherapy became commonplace in resourced nations. An unintended consequence of many of these advances was that they resulted in immune impairment. Similarly, HIV/AIDS, which emerged in the late 1970's also produced profound immune impairment. Unexpectedly, the prevailing view that microbes were the sole perpetrators of virulence was untenable. Microbes that were rarely if ever associated with disease emerged as major causes of disease in people with impaired immunity. This phenomenon revealed that available explanations for microbial infectiveness and virulence were flawed. In this review, we discuss the question 'what is infectiveness' based on the tenets of the Damage-response framework.