Staphylococcus aureus remains one of the leading causes of morbidity and mortality worldwide. This is to a large extent due to antibiotic-resistant strains, in particular methicillin-resistant S. aureus (MRSA). While the toll of invasive MRSA infections appears to decrease in U.S. hospitals, the rate of community-associated MRSA infections remains constant and there is a surge of MRSA in many other countries, a situation that calls for continuing if not increased efforts to find novel strategies to combat MRSA infections. This review provides an overview of current investigational drugs and therapeutic antibodies against S. aureus in early clinical development (up to phase II clinical development). It includes a short description of the mechanism of action and a presentation of microbiological and clinical data. Increased recent antibiotic development efforts and results from pathogenesis research have led to several new antibiotics and therapies, such as anti-virulence drugs, as well as a more informed selection of targets for vaccination efforts against MRSA. This developing portfolio of novel anti-staphylococcal drugs will hopefully provide us with additional and more efficient ways to combat MRSA infections in the near future and prevent us from running out of treatment options, even if new resistances arise.