Resistance against the major currently available anthelmintics has reached a critical level in many small ruminant herds world-wide, and is increasingly becoming a problem in horses and cattle. Therefore, new products with different modes of action are urgently needed. Recently, such a new class of compounds, the anthelmintically active cyclooctadepsipeptides, was described. Here, the effects of cyclooctadepsipeptides on benzimidazole-, levamisole- and ivermectin-resistant populations of Haemonchus contortus in sheep as well as an ivermectin-resistant Cooperia oncophora population in cattle were studied. Experimentally infected sheep and cattle were used. Animals were treated orally, subcutaneously, or intravenously with cyclooctadepsipeptides. The anthelmintic effects were assessed by means of fecal egg count reductions and/or worm count reductions. Both, PF1022A and emodepside were found to be fully effective against these parasite populations. These findings confirm that this new class of compounds acts by a different mode of action compared to the above-mentioned anthelmintics.