Natural killer (NK) cells provide the first line of defence against pathogens and tumors. Their activation status is regulated by pro-inflammatory cytokines and by ligands that either target inhibitory or activating cell surface receptors belonging to the immunoglobulin-like, C-type lectin or natural cytotoxicity receptor families. Apart from non-classical HLA-E, membrane-bound heat shock protein 70 (Hsp70) has been identified as a tumor-specific recognition structure for NK cells expressing high amounts of the C-type lectin receptor CD94, acting as one component of an activating heterodimeric receptor complex. Full-length Hsp70 protein (Hsp70) or the 14-mer Hsp70 peptide T-K-D-N-N-L-L-G-R-F-E-L-S-G (TKD) in combination with pro-inflammatory cytokines enhances the cytolytic activity of NK cells towards Hsp70 membrane-positive tumors. Based on these findings cytokine/TKD-activated NK cells were adoptively transferred in tumor patients. These findings were compared to results of clinical trials using cytokine-activated NK cells.