Over the past century, a number of synthetic antimicrobial agents have been discovered and developed, but drug resistance and toxicity are still the major hindrances to gaining successful therapeutic outcomes in many instances. Herbal medicines may represent a safe and useful supplement to existing chemotherapeutic therapies for the management of infectious diseases. Ganoderma has traditionally been used to treat chronic infectious diseases, such as chronic hepatitis and bronchitis in Asia, when it is administered alone or more often in combination with chemotherapeutic agents. Preclinical (in vitro and in vivo animal) studies indicate that Ganoderma exhibits a broad spectrum of antibacterial and antiviral activities, whereas data in human beings are scanty. Polysaccharides or triterpenoids from Ganoderma showed activities against Herpes simple virus, Hepatitis B virus, HIV, and Epstein-Barr virus in vitro or in animal models. Ganoderma species also contain antibacterial constituents inhibiting gram-positive and/or gram-negative bacteria in vitro. However, it is difficult to extrapolate these findings to humans, as most of these preclinical studies were conducted under optimized conditions with the use of high doses of Ganoderma components. A double-blind, randomized, placebo-controlled clinical study indicated that treatment of hepatitis B patients with G. lucidum polysaccharides at 5400 mg/day for 12 weeks resulted in significantly decreased serum HBV DNA and hepatitis B e antigen (HbeAg) levels. The mechanisms for the antimicrobial and antiviral activities of Ganoderma are largely undefined. Currently available data do not support the use of Ganoderma as an antibiotic, but it may play an adjunct role for the management of bacterial and viral infection. Further studies are needed in humans.