Multidrug-resistantStaphylococcus epidermidis(MDRSE) is responsible for difficult-to-treat infections in humans and hospital-acquired-infections. This review discusses the epidemiology, microbiology, diagnosis, and treatment of MDRSE infection and identifies knowledge gaps. By using the search term “pan resistantStaphylococcus epidermidis” OR “multi-drug resistantStaphylococcus epidermidis” OR “multidrug-resistant lineages ofStaphylococcus epidermidis”, a total of 64 records have been identified from various previously published studies. The proportion of methicillin resistance inS. epidermidishas been reported to be as high as 92%. Several studies across the world have aimed to detect the main phylogenetic lineages and antibiotically resistant genes through culture, mass spectrometry, and genomic analysis. Molecular biology tools are now available for the identification ofS. epidermidisand its drug resistance mechanisms, especially in blood cultures. However, understanding the distinction between a simple colonization and a bloodstream infection (BSI) caused byS. epidermidisis still a challenge for clinicians. Some important parameters to keep in mind are the number of positive samples, the symptoms and signs of the patient, the comorbidities of the patient, the presence of central venous catheter (CVC) or other medical device, and the resistance phenotype of the organism. The agent of choice for empiric parenteral therapy is vancomycin. Other treatment options, depending on different clinical settings, may include teicoplanin, daptomycin, oxazolidinones, long-acting lipoglycopeptides, and ceftaroline. For patients withS. epidermidisinfections associated with the presence of an indwelling device, assessment regarding whether the device warrants removal is an important component of management. This study provides an overview of the MDRSE infection. Further studies are needed to explore and establish the most correct form of management of this infection.