The most common group of mitochondrial disease is due to mutations within the mitochondrial DNA polymerase, polymerase gamma 1 ("POLG"). This gene product is responsible for replication and repair of the small mitochondrial DNA genome. The structure-function relationship of this gene product produces a wide variety of diseases that at times, seems to defy the common perceptions of genetics. The unique features of mitochondrial physiology are in part responsible, but "POLG" structure and function add to the conundrum of how one gene product can demonstrate autosomal recessive and autosomal dominant transmission, while also being responsible for pharmacogenetic disease, and exhibiting strong gene-environment interactions. The wide spectrum of clinical manifestations of "POLG" disease can arise from infancy to old age. The modulation of clinical findings relate in part to the molecular architecture of the POLG protein. "POLG" has three distinct molecular domains: exonuclease, linker, and polymerase domains. Most of the mutations leading to dominant forms of "POLG" disease are located in the Polymerase domain. Mutations leading to recessive inheritance are distributed in all three domains of the gene. Environmental factors like valproic acid and infection can unmask "POLG" disease, causing it to occur earlier in life than when not exposed to these factors. Other drugs like nucleoside reverse transcriptase inhibitors can produce genotype-specific "POLG" pharmacogenetic disease. Our current state of "POLG" understanding cannot account for many features of "POLG" disease. There is no answer for why the same mutation can give rise to varying diseases, disease severity, and age of onset. We introduce the term Ecogenetics in the context these features of "POLG" disease, to emphasize the important interactions between genes and environment in determining the expression of mitochondrial disease. In this article, we identify some of the key features that will help the reader understand "POLG" pathophysiology. When possible, we also identify genotype-phenotype relationships, give clues for diagnosis, and summarize the major clinical phenotypes in the spectrum of "POLG" disease presenting from birth to old age. (Contains 4 tables and 1 figure.)