Abstract: The infection of human mucosal surfaces by bacteria accounts for some of the most common and costly diseases worldwide. Currently, mucosal infections are controlled by antibiotics or other general biocides. Although effective, antibiotics are indiscriminant, killing both pathogenic and beneficial normal flora. Negative clinical consequences often result when the ecology of the normal flora are disrupted, underscoring the need for a narrow-spectrum therapeutic capable of eliminating a targeted pathogen with little impact on the normal flora. To address this problem, we designed a novel class of antibiotics, known as specifically (or selectively)- targeted antimicrobial peptides (STAMPs). These chimeric molecules consist of functionally independent, yet conjoined, targeting and antimicrobial domains within the sequence of a linear peptide. Potential STAMP targeting regions were pre-selected as independent molecules by their ability to bind discriminately to the surface of targeted pathogenic bacteria. Both de novo rationally designed and natural species-specific pheromone-based peptides were successfully incorporated as STAMP targeting domains, and when conjoined with a normally wide-spectrum antimicrobial peptide, were capable of conferring selective pathogen recognition. Moreover, we demonstrated that targeting domains can be conjoined to different antimicrobial peptides, thereby constructing several unique but functionally analogous STAMPs with identical specificities. Our prototype STAMPs were effective in selectively eliminating both Gram-positive and Gram-negative mucosal pathogens from mixed planktonic cultures and biofilm communities without impacting closely-related normal flora. The results presented here strongly indicate that STAMPs are functional 'smart' antimicrobials, and may be useful as probiotic therapeutics against mucosal pathogens.