Pathogens use type VI secretion systems (T6SSs) to transport proteins into the environment or host cells in response to external stimuli. T6SSs are tightly regulated together with other virulence determinants such as type III secretion systems, quorum sensing (QS), and flagella synthesis. Five pathogens (Salmonella enterica, Edwardsiella tarda, Aeromonas hydrophila, Vibrio cholerae, and Pseudomonas aeruginosa) are examined for crosstalk proteins (global regulators) that connect T6SSs to other virulence determinants. Common transcriptional regulators (TRs) include two component systems (i.e. PhoPQ), σ54 and σ54-dependent TRs (i.e. VasH), and QS regulators. Greater understanding of this integral communication network will define what is essential for bacterial pathogenesis.