Cancer is the second leading cause of human deaths in the USA. Despite continuous efforts to treat cancer over the past 50 years, human mortality rates have not decreased significantly. Natural products, such as lichens, have been good sources of anticancer drugs. This study reports the cytotoxic activity of crude extracts of 17 lichen species against Burkitt's lymphoma (Raji) cells. Out of the 17 lichen species, extracts from 14 species showed cytotoxicity against Raji cells. On the basis of IC50 values, we selectedXanthoparmelia chlorochroaandTuckermannopsis ciliaristo study the mechanism of cell death. Viability of normal lymphocytes was not affected by the extracts ofX. chlorochroaandT. ciliaris. We found that extracts from both lichens decreased proliferation, accumulated cells at the G0/G1 stage, and caused apoptosis in a dose-dependent manner. Both lichen extracts also caused upregulation of p53. TheT. ciliarisextract upregulated the expression of TK1 butX. chlorochroadid not. We also found that usnic, salazinic, constictic, and norstictic acids were present in the extract ofX. chlorochroa, whereas protolichesterinic acid inT. ciliaris extracts. Our data demonstrate that lichen extracts merit further research as a potential source of anticancer drugs. Copyright © 2014 John Wiley & Sons, Ltd.