Biofilms form in moist environments when micro-organisms grow on surfaces in a self-produced polymeric matrix. From a clinical perspective, the most notable feature of biofilms is their markedly decreased susceptibility to antimicrobials in comparison to their dispersed (or planktonic) counterparts. While it seems intuitively correct that biofilm recalcitrance occurs principally through the failure of antimicrobial penetration, the true basis of the phenomenon is more complex. As well as the retardation of antimicrobial diffusion, biofilms often exhibit localised phenotypic heterogeneity—in particular, growth rate variation in which slow-growing or dormant cells are found to be inherently less sensitive to antimicrobials. Persister cells, which occur as a small proportion of the total population, are also believed to repopulate the biofilm following sub-effective antimicrobial treatments. In summary, no single mechanism can fully account for biofilm recalcitrance; rather, multiple mechanisms are responsible. This chapter provides a concise overview of the phenomenon of biofilm recalcitrance.