<p>Endolysins, which are peptidoglycan hydrolases derived from bacteriophages, are expected to innovate antimicrobial treatment. More specifically, several endolysins that target gram-positive bacteria are currently being evaluated in clinical trials, reflecting increasing interest in their therapeutic application. Research involving endolysins has expanded exponentially over the last 20&#xa0;years, which has resulted in a substantial diversification. With most of the field having focused on endolysin discovery, biochemical characterization and applying protein engineering strategies, it remains unclear whether endolysins should eventually be implemented as stand-alone antimicrobials or alongside standard-of-care antibiotics, an ambiguity that is also reflected in the endolysins that are currently being evaluated in clinical trials. This selective review, inspired by a selection of preclinical studies in which endolysin monotherapy had inconsistent outcomes, concludes that endolysins hold their greatest therapeutic potential when used in combination with standard-of-care antibiotics, except in cases, where therapy is limited to a local or topical application only. In the latter, antibiotic supplementation can negatively impact the microbiome that is essential to maintain, for example, skin, ear, eye, nasopharyngeal, gut and vaginal homeostasis. By combining endolysins with antibiotics that preferably target the bacterial cell wall or membrane, such as β-lactams, as well as lipo- and glycopeptides, synergistic or additive effects can be exploited that substantially reduce minimal inhibitory concentrations, restoring antibiotic susceptibility in otherwise resistant bacteria. Overall, this selective review asserts that endolysins may be best implemented alongside standard-of-care antibiotics, as this may lead to more consistent and reliable clinical outcomes, particularly in systemic infections.</p>