Emerging resistance to all available antibiotics highlights the need to develop new antibiotics with novel mechanisms of action. Most of the currently used antibiotics target Gram-positive bacteria while Gram-negative bacteria easily bypass the action of most drug molecules because of their unique outer membrane. This additional layer acts as a potent barrier restricting the entry of compounds into the cell. In this scenario, several approaches have been elucidated to increase the accumulation of compounds into Gram-negative bacteria. This review includes a brief description of the physicochemical properties that can aid compounds to enter and accumulate in Gram-negative bacteria and covers different strategies to target or bypass the outer membrane-mediated barrier in Gram-negative bacterial pathogens.