Studies on interactions between natural killer (NK) cells and freshly isolated human tumor cells are still relatively scarce. With respect to the understanding of NK cell interactions with human tumors in vivo, and attempts to better predict the outcome of NK cell-mediated adoptive immunotherapy, such studies merit further attention. They may provide information that is not readily evident through studies of human tumor cell lines established through long-term culturing in vitro. The latter undergo several changes and adaptations to their environment, many of which may affect interactions with NK cells. Studies of NK cell interactions with freshly explanted human tumors, however, are cumbersome for several reasons including; often poor accessibility of human tumor material per se, difficulties in sample processing and contamination of tumors with nontumor cells, spontaneous apoptosis of tumor cells, as well as methodological challenges in assessing tumor cell lysis following interactions with NK cells. Here, we review the current knowledge on NK cell interaction with freshly isolated human tumors.