Cardiolipin (CL) is a phospholipid with many unique characteristics. CL is 
synthesized in the mitochondria and resides almost exclusively within the 
mitochondrial inner membrane. Unlike most phospholipids that have two fatty acyl 
chains, CL possesses four fatty acyl chains resulting in unique biophysical 
characteristics that impact several biological processes including membrane 
fission and fusion. In addition, several proteins directly bind CL including 
proteins within the electron transport chain, the ADP/ATP carrier, and proteins 
that mediate mitophagy. Tafazzin is an enzyme that remodels saturated fatty acyl 
chains within CL to unsaturated fatty acyl chains, loss of function mutations in 
the TAZ gene encoding tafazzin are causal for the inherited cardiomyopathy Barth 
syndrome. Cells from Barth syndrome patients as well as several models of Barth 
have reduced mitochondrial functions including impaired electron transport chain 
function and increased reactive oxygen species (ROS) production. Mitochondria in 
cells from Barth syndrome patients, as well as several model organism mimics of 
Barth syndrome, are large and lack cristae consistent with the recently 
described role of CL participating in the generation of mitochondrial membrane 
contact sites. Cells with an inactive TAZ gene have also been shown to have a 
decreased capacity to undergo mitophagy when faced with stresses such as 
increased ROS or decreased mitochondrial quality control. This review describes 
CL metabolism and how defects in CL metabolism cause Barth syndrome, the 
etiology of Barth syndrome, and known modifiers of Barth syndrome phenotypes 
some of which could be explored for their amelioration of Barth syndrome in 
higher organisms.