Hospital-acquired infections are associated with prolonged hospitalization and an increase in both healthcare costs and resources. Advances in sophisticated medical procedures, an increase in the number of immunocompromised patients, and the continued emergence of resistance to conventional antibiotic therapy has created a need for alternative strategies to prevent and treat infectious bacterial diseases. Immunoprevention and immunotherapy targeting microbial surface components recognizing adhesive matrix molecule (MSCRAMM) proteins are viable approaches to potentially impede bacterial adherence, eliminate colonization, and minimize hematogenous dissemination, thereby halting the inception and progression of infection. This review summarizes several investigative efforts where staphylococcal MSCRAMM proteins are being utilized in the design of subunit vaccines and in the development of innovative therapeutic strategies that could be implemented following the onset of infection to manage severe and life-threatening disease.