Previously considered a human commensal, Staphylococcus epidermidis is a frequent cause of nosocomial infections and the most common cause of device-related infections. Because the expression of toxins and other obvious virulence factors is less in S. epidermidis, the biofilm-forming capacity is its major virulence factor. Biofilm growth is characterized by high resistance to antimicrobial agents and host immune responses, making biofilm eradication tremendously difficult. The increasing prevalence of multidrug-resistant S. epidermidis strains additionally hampers antimicrobial therapy. Therefore, immunoprophylaxis and immunotherapy targeting factors expressed at some point in biofilm formation might offer new tools to combat S. epidermidis infections. So far, a limited number of targets have been examined for their immunotherapeutic potential. In this review, we focus on the already tested and possible targets for vaccine development, discuss the accompanying challenges and speculate on future possibilities with respect to immunotherapeutic solutions to deal with S. epidermidis infections.