Over the last several years, surprising results have appeared that the semi-synthetic tetracycline derivatives minocycline and doxycycline have biological properties independent of their anti-microbial action. These newly discovered properties include the inhibition of processes including reactive oxygen species production by neutrophils, inducible nitric oxide synthase (iNOS) induction, protein tyrosine nitration, matrix metalloproteases activity, tumor growth, and bone resorption. Given that pathological processes in the mammalian central nervous system are often associated with an inflammatory response, the use of semi-synthetic tetracycline derivatives in models of human neurological disease has been investigated. A number of studies have demonstrated that these agents inhibit the morphological and functional activation of microglial in vitro and in vivo. This inhibition is associated with a decrease in the expression of several inflammatory mediators including IL-1β converting enzyme and iNOS. These anti-inflammatory effects are also associated with an inhibition in caspase-dependent and caspase-independent apoptotic pathways. Several studies have demonstrated that tetracycline derivatives decrease cell death and neurological dysfunction as well as prolong animal survival in models of human neurological disease including cerebral ischemia, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, and experimental autoimmune encephalomyelitis. This brief review summarizes the research on these recently identified properties of tetracycline derivatives. We also present data using minocycline in the treatment of a virus-induced animal model of multiple sclerosis.