Using cytotoxicity against the KB cancer cell line (ATCC CCL17) as a lead, bioactivity-guided fractionation of the MeOH-soluble part of the DCM extract of Warionia saharae leaves led to the isolation of six new cytotoxic guaianolide type sesquiterpene lactones (1-6). Besides two guaianolides showing the common 6,7-trans fused lactone ring (3 and 4), four compounds exhibiting the more rare 6,7-cis configuration (1,2 and 5,6) were also isolated. Compounds 1, 2, 5, and 6 showed an unprecedented ether bridge between C-2 and C-4. The structures were deduced from extensive 1D and 2D NMR spectroscopy ((1)H, (13)C, DQF-COSY, HSQC, HMBC, ROESY), as well as mass spectrometry (EI and HR-MALDI). Cytotoxicity testing against the KB cancer cell line revealed IC(50) values of 1.0 (1), 4.5 (2), 1.7 (3), 2.0 (4), 3.3 (5), and 5.5 (6) microg/mL.