The spread of antibiotic resistance genes has created public concerns leading to new laws that restrict the use of antibiotics as growth promoters in domestic and meat-producing animals in several countries around the world. In this chapter, the safety and efficacy of individual monocultures for prophylactic and/or therapeutic efficacy against Salmonella infections in poultry under both laboratory and field conditions are summarized. In addition, the development of novel, cost-effective, feed-stable, direct-fed microbials with potential for widespread utilization and improved production, delivery and clinical efficacy for animal use are presented. Following an introduction, a section on the use of probiotics in poultry is presented; a discussion on probiotics and inflammation is also provided. The risks on the overuse of antibiotics are discussed, and the chapter concludes with an introduction to the use of direct-fed microbials in commercial poultry diets.