Recent decades have seen a rapid increase in reported toxic effects of drugs and pollutants on mitochondria. Researchers have also documented many genetic differences leading to mitochondrial diseases, currently reported to affect ∼1 person in 4,300, creating a large number of potential gene-environment interactions in mitochondrial toxicity. We briefly review this history, and then highlight cutting-edge areas of mitochondrial research including the role of mitochondrial reactive oxygen species in signaling; increased understanding of fundamental biological processes involved in mitochondrial homeostasis (DNA maintenance and mutagenesis, mitochondrial stress response pathways, fusion and fission, autophagy and biogenesis, and exocytosis); systemic effects resulting from mitochondrial stresses in specific cell types; mitochondrial involvement in immune function; the growing evidence of long-term effects of mitochondrial toxicity; mitochondrial-epigenetic cross-talk; and newer approaches to test chemicals for mitochondrial toxicity. We also discuss the potential importance of hormetic effects of mitochondrial stressors. Finally, we comment on future areas of research we consider critical for mitochondrial toxicology, including increased integration of clinical, experimental laboratory, and epidemiological (human and wildlife) studies; improved understanding of biomarkers in the human population; and incorporation of other factors that affect mitochondria, such as diet, exercise, age, and nonchemical stressors. One of the most common signs of MT is muscle weakness (myopathy). If muscle cells can’t get enough energy through cellular respiration, they have to get energy without oxygen. This “anaerobic” energy production creates lactic acid as a waste product. Mitochondria have an enzyme that helps them multiply. This enzyme is called DNA polymerase gamma, or “pol gamma.” It is very similar to HIV’s reverse transcriptase enzyme. Unfortunately, this also means that some drugs we use to inhibit reverse transcriptase can also inhibit pol gamma. When this happens, fewer new mitochondria may be produced. Some nucleoside analog reverse transcriptase inhibitors (AZT, 3TC, ddI, d4T) inhibit pol gamma to some degree. MT is more likely to occur the longer you take these drugs. Different medications build up in different parts of the body. This could explain how MT caused by different drugs can lead to side effects in different parts of the body. We know that MT can cause muscle weakness in people taking AZT. It is probably the cause of “fatty liver” (hepatic steatosis) and high levels of lactic acid that can be caused by all of the nukes. Unfortunately, there is very little research on how much mitochondrial damage each ARV causes to different parts of the body. We also don’t know which combinations of drugs cause the most MT. Researchers know how to measure the number of mitochondria in different cells, compared to normal. However, they don’t know many mitochondria a cell can lose before there are problems.