AbstractFirst paragraph (this article has no abstract) There is nothing more frustrating than reaching the end of a jigsaw puzzle to find that some of the pieces are missing. There are certainly areas of immunology where the same problem applies and despite major advances there are some pieces of the jigsaw that are still missing after many years. When I was asked to think of some of the questions that remain unanswered in the cell biology of the immune system, three leapt to mind. One concerns antigen presentation, another cytotoxic T lymphocyte (CTL)- or natural killer (NK)-cell-mediated killing, and the third a mechanism of apoptosis. Although seemingly disparate, each one of these boils down to a question of how proteins cross membranes to reach the cytoplasm.