Parkinson's disease (PD) is the second most common neurodegenerative disorder 
that is characterized by two major neuropathological hallmarks: the degeneration 
of dopaminergic neurons in the substantia nigra (SN) and the presence of Lewy 
bodies in the surviving SN neurons, as well as other regions of the central and 
peripheral nervous system. Animal models have been invaluable tools for 
investigating the underlying mechanisms of the pathogenesis of PD and testing 
new potential symptomatic, neuroprotective and neurorestorative therapies. 
However, the usefulness of these models is dependent on how precisely they 
replicate the features of clinical PD with some studies now employing combined 
gene-environment models to replicate more of the affected pathways. The rotenone 
model of PD has become of great interest following the seminal paper by the 
Greenamyre group in 2000 (Betarbet et al., 2000). This paper reported for the 
first time that systemic rotenone was able to reproduce the two pathological 
hallmarks of PD as well as certain parkinsonian motor deficits. Since 2000, many 
research groups have actively used the rotenone model worldwide. This paper will 
review rotenone models, focusing upon their ability to reproduce the two 
pathological hallmarks of PD, motor deficits, extranigral pathology and 
non-motor symptoms. We will also summarize the recent advances in 
neuroprotective therapies, focusing on those that investigated non-motor 
symptoms and review rotenone models used in combination with PD genetic models 
to investigate gene-environment interactions.