•Salmonella bacteria causes a different array of diseases and infection can be acute or chronic and can be limited to the intestine or distributed systemically.•The immune response to systemic Salmonella infection is potent diverse and includes both innate and adaptive immune aspects.•Salmonella uses multiple mechanisms to subvert or modulate the immune response directed against it. Salmonella infection causes morbidity and mortality throughout the world with the host immune response varying depending on whether the infection is acute and limited, or systemic and chronic. Additionally, Salmonella bacteria have evolved multiple mechanisms to avoid or subvert immunity to its own benefit and often the anatomical location of infection plays a role in both the immune response and bacterial fate. Here, we provide an overview of the interplay between the immune system and Salmonella, while discussing how different host and bacterial factors influence the outcome of infection.