The number of anti-cancer antibodies in therapy and in clinical trials is increasing gradually while their curative efficacy remains rather limited due to the resistance of tumor cells to complement-dependent cytotoxicity (CDC). An updated review of the various defense mechanisms complement is confronting when tackling a tumor cell is presented. The mechanisms discussed are: membrane and secreted complement regulatory proteins, heat shock proteins, extracellular proteases and protein kinases, cell surface sialylation and intracellular survival anti-lytic signals. Projected treatment strategies are depicted for each of the complement resistance mechanisms. It is conceivable that the therapeutic capacity of anti-cancer antibodies will be amplified once combined with a reagent that sensitizes the cancer cells to CDC.