The type VI Secretion System (T6SS) is a tool for Gram-negative pathogens to interact with other bacteria as well as with the eukaryotic host cell. While the role of T6SS in interbacterial interactions has drawn much attention in recent years, research into the T6SS as a human virulence factor continues at a slower pace. Nevertheless, T6SS has been shown to interfere with eukaryotic host cell immunity at several levels, ranging from direct attack of the host cell to attenuation of disease, allowing the pathogen to survive longer in the host environment. In this review, we aim to give a comprehensive overview focused on the ways bacteria use their T6SS in the modulation of mammalian host cell immunity. While doing so, we attempt to describe potential new avenues of research, as well as outline the ways in which T6SS could become a therapeutic target allowing to circumvent existing antibiotic resistance. Although much work remains to be done, a better comprehension of the T6SS mechanisms of action will undoubtedly lead to new strategies to counteract T6SS-bearing pathogens.