Heavy metals present in the environment can cause a variety of injury symptoms in various organisms including lichens. Most studies examined metal-induced stress under controlled laboratory conditions, and little is known about actual response of lichens in their natural habitat. This study aims to recognize the effect of heavy metal accumulation (total and intracellular) on lichen physiological and biochemical parameters specifically related to the functioning of fungal component. Cladonia rei was used as a model species due to its common occurrence both in unpolluted and extremely polluted sites. We observed a decline in the fungal metabolism which was expressed by a decrease in ergosterol content and an increase in cell membrane damage as a result of increased Zn, Cd, Cu and Ni accumulation. Additionally, the results indicated that increased accumulation of xenobiotics (Pb and As) caused reduction of glutathione (GSH) concentrations and increased membrane lipid peroxidation. Therefore, we conclude that GSH does not provide high oxidative stress protection in C. rei which is somewhat against its insensitivity to pollution. The reduced pool of GSH could be explained by its oxidation to glutathione disulphide induced by heavy metal stress or its use for phytochelatin (PC) synthesis. The content of secondary metabolites was not related to heavy metal accumulation and remained at a relatively stable level. This indicates that the decline in the physiological condition did not weaken the mycobiont of C. rei enough to inhibit the synthesis of secondary metabolites and their precursors were supplied at a sufficient level. Thus, the potential function of main secondary metabolites as extracellular metal immobilizers and antioxidants is still possible even in individuals growing at extremely polluted sites. Despite the evident heavy metal stress, C. rei copes well and spreads easily through extremely polluted environments, which underlines its unique pioneering abilities in highly disturbed sites.