Hospital-acquired pneumonia represents one of the most difficult treatment challenges in infectious diseases. Many studies suggest that the timely administration of appropriate, pathogen-directed therapy can be lifesaving. Because results of culture and antimicrobial susceptibility testing can take 48 h or longer, physicians currently rely on clinical, epidemiological, and demographic factors to assist with the choice of empiric therapy for antibiotic-resistant pathogens. At present, a number of rapid molecular tests are being developed that identify pathogens and the presence of genetic determinants of antimicrobial resistance (eg, GeneXpert [Cepheid], ResPlex [Qiagen], FilmArray [Idaho Technologies], and Microarray [Check-Points]). In this review, the potential impact that molecular diagnostics has to identify and characterize pathogens that cause hospital-acquired bacterial pneumonia at an early stage is examined. In addition, a perspective on a novel technology, polymerase chain reaction followed by electrospray ionization mass spectrometry, is presented, and its prospective use in the diagnosis of pneumonia is also discussed. The complexities of the pulmonary microbiome represent a novel challenge to clinicians, but many questions still remain even as these technologies improve.