Resistance to antibiotics is one of the greatest dangers to the humanity, according to the World Health Organization. To reduce the amount of used antibiotics, various targeted drug delivery is considered, e.g., biopolymeric micro- or nanoparticles, electrospun nanofibers, or self-emulsifying drug delivery systems. In the case of hydrophilic antibiotics, there is an issue of relatively low encapsulation efficiencies and too rapid release, due to chemical character impairment (hydrophobic carrier – hydrophilic antibiotic). It results in not only lower clinical success rate, but also in creating a huge antibiotic waste when the manufacturing process is converted to the industrial conditions. A possible solution to overcome these problems is changing the chemical character of the antibiotics by a simple reaction of ion pairing with either cationic or ionic surfactants that may decrease water solubility of antibiotics without any loss, or with even better, bactericidal properties. This approach increases encapsulation efficiency up to nearly 100%. As the result, lower doses of antibiotics can be used in drug delivery systems that provide a more sustainable release. However, there is a risk of a higher toxicity due to the presence of surfactants and the origin of improved antibacterial properties have not yet been fully explained. Herein, we present the review of the current achievements in the field of antibiotics hydrophobized by hydrophobic ion pairing (HIP) for various drug delivery systems with the special regard to the antibacterial properties and biocompatibility.