The microbiological diagnosis of pneumonia is imperfect in the sense that a microbiological agent is incriminated in less than about a third of all cases. The initial antimicrobial therapy of community-acquired pneumonia is necessarily empiric. This chapter discusses the issues involved in microbiological diagnosis, the interpretation of sputum tests and the implications of the absence of a dominant organism or a poor yield on sputum testing. The chapter also explores the circumstances that should drive more aggressive testing, the application of urinary antigen tests and modern molecular techniques in diagnosis, and the factors that should be taken into consideration before embarking on empirical therapy pending the results of laboratory tests.