Complement-mediated tumor cell lysis is hampered by several protective mechanisms and represent a major barrier for successful antibody-based cancer immunotherapy. Basal mechanisms of resistance include the (over)expression of membrane-associated complement regulatory proteins, such as CD55 (DAF, Decay-Accelerating Factor), CD46 (MCP, Membrane Cofactor Protein) and CD59, on malignant cells. To generate a protective microenvironment, tumor cells secrete several soluble complement inhibitors and express on their surface ecto-proteases that degrade complement proteins or ecto-protein kinases which impair by phosphorylation the functional activity of certain complement components. Increased sialic acid expression also confers complement resistance to cancer cells and has been correlated with increased metastatic activity in certain cancers. Tumor cell protection can be also induced or augmented upon stimulation with cytokines, hormones, drugs or even with sublytic doses of complement and other pore-forming molecules. Attempts are now being made to counteract these resistance mechanisms, including a targeted neutralization of surface complememt regulation on tumor cells, either by bispecific anti-tumor-anti-complement regulator antibodies or by gene silencing (antisense oligonucleotides , siRNA). Understanding the complex molecular mechanisms involved in basal and induced tumor cell resistance to complement is essential for the development of strategies to interfere with these evasion mechanisms and for effectively targeting the cytotoxic activity of complement to cancer cells in antibody-based immunotherapy.