Salmonella causes an estimated 1.3 million human foodborne illnesses and more than 500 deaths each year in the United States, representing an annual estimated cost to the economy of approximately $2.4 billion. Salmonella enterica comprises more than 2,500 serotypes. With this genetic and environmental diversity, serotypes are adapted to live in a variety of hosts, which may or may not manifest with clinical illness. Thus, Salmonella presents a multifaceted threat to food production and safety. Salmonella have been isolated from all food animals and can cause morbidity and mortality in swine, cattle, sheep, and poultry. The link between human salmonellosis and host animals is most clear in poultry. During the early part of the 20th century, a successful campaign was waged to eliminate fowl typhoid caused by Salmonella Gallinarum/Pullorum. Microbial ecology is much like macroecology; environmental niches are filled by adapted and specialized species. Elimination of S. Gallinarum cleared a niche in the on-farm and intestinal microbial ecology that was quickly exploited by Salmonella Enteritidis and other serotypes that live in other hosts, such as rodents. In the years since, human salmonellosis cases linked to poultry have increased to the point that uncooked chicken and eggs are regarded as toxic in the zeitgeist. Salmonellosis caused by poultry products have increased significantly in the past 5 yr, leading to a USDA Food Safety and Inspection Service “Salmonella Attack Plan” that aims to reduce the incidence of Salmonella in chickens below the current 19%. The prevalence of Salmonella in swine and cattle is lower, but still poses a threat to food safety and production efficiency. Thus, approaches to reducing Salmonella in animals must take into consideration that the microbial ecology of the animal is a critical factor that should be accounted for when designing intervention strategies. Use of competitive exclusion, sodium chlorate, vaccination, and bacteriophage are all strategies that can reduce Salmonella in the live animal, but it is vital to understand how they function so that we do not invoke the law of unintended consequences.