Giuseppe Attardi was neither a neurologist nor a practicing physician, though he obtained his medical degree from the University of Padua in 1947. However, his pioneering work in mitochondrial biology had a tremendous effect on our understanding of human mitochondrial diseases. Therefore, his death, which abruptly interrupted a long but still vibrant research career, is as much a loss for biology in general as it is for neurology. Dr Attardi's monumental contributions to our knowledge of the “other genome,” mitochondrial DNA (mtDNA), include the discovery of mitochondrial RNA (which accounts for only 0.5% of the total cellular RNA [a very important needle in a very big haystack]), the characterization of mitochondrial ribosomes, the definition of mtDNA transcription, the punctuation role of mitochondrial transfer RNA in the processing of the polycistronic precursor RNA, and the identification of all 13 proteins encoded by mtDNA. More directly, when the first pathogenic mutations in human mtDNA were described in 1988, Dr Attardi understood that obtaining an animal model of mtDNA-related diseases was going to be a formidable if not insurmountable task, and he, together with a then graduate student Michael P. King, perfected an ingenious in vitro model that allowed one to repopulate permanent human cell lines emptied of their mtDNA (rho0 cells) with mitochondria from patients harboring mtDNA mutations. This system has been widely used and has provided important information on the pathogenic nature, threshold, and (to a lesser extent) mechanism of different mtDNA mutations.