The high susceptibility of dopaminergic (DA) neurons to cellular stress is regarded as a primary cause of Parkinson’s disease. Here we investigate the role of the serum response factor (SRF), an important regulator of anti-apoptotic responses, for the survival of DA neurons in mice. We show that loss of SRF in DA neurons does not affect their viability and does not influence dopamine-dependent behaviors. However, ablation of SRF causes exacerbated sensitivity to 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP), leading to significantly greater loss of DA neurons in the substantia nigra, compared with DA neurons located in the ventral tegmental area. In addition, loss of SRF decreases levels of the anti-apoptotic proteins brain-derived neurotrophic factor (BDNF) and Bcl-2, a plausible underlying cause of increased sensitivity to oxidative stress. These observations support the notion that dysfunction of the SRF-activating mitogen-associated kinase pathway may be part of Parkinson’s disease etiology.