Infection results when an imbalance occurs between the mechanisms that microorganisms employ to induce infection and the complex physiological response systems that are used by a host to prevent such infections. Infection can be distinguished from colonization, which is when a microorganism occupies an ecological niche in a host and grows but does not overcome host resistance or cause invasive disease. In the past 20 years, research regarding increases in microbial virulence induced by changes in exotoxin production or surface antigenic construction has led to a better understanding of determinants of virulence. We have also come to understand the interactions within the immune system that serve to foster integration of host defenses, and how HIV, the immune-altering prototypic infection of the 20th century, modifies and defeats those defenses. Additionally, we are now able to distinguish between (a) innate immunity—those elements of natural defense that are activated by cell injury or death—and (b) adaptive immunity (cellular and humoral), which can be enhanced and have the property of immunological memory. In many circumstances, we can enhance or support a state of vigorous adaptive immunity and terminate or prevent infection. Understanding these defense mechanisms is essential to the design and implementation of effective infection prevention and control programs in healthcare settings.