Lipodystrophy (LD) with varying degrees of lipohypertrophy, lipoatrophy, hyperlipidemia, and insulin resistance is one of the complications of highly active antiretroviral therapy (HAART) and occurs in one to 33 % of HAART-treated, HIV infected children. We summarize the data on the role of leptin, adiponectin, the growth hormone axis, glucocorticoids, sterol response element binding protein 1c (SREBP-1c), the tumor necrosis factor alpha axis (TNF-alpha), interleukin-6 (IL-6), interleukin- 18 (IL-18), interferon-alpha (IFN-alpha), tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI-1) in the pathophysiology of LD. Adiponectin levels are generally decreased in LD, whereas leptin levels are increased. Systemic cortisol levels are not elevated in LD, even though glucocorticoids seem to play an important role in LD and the phenotype can be reminiscent of Cushing syndrome. GH resistance in LD needs to be better characterized. While some cytokines show promise as markers for LD, it is difficult to tell whether their derangement is a cause of or the effect of LD.