Parkinson's disease (PD) is a chronic movement disorder typically coupled to progressive degeneration of dopaminergic neurons in the substantia nigra (SN). The treatments currently available are satisfactory for symptomatic management, but the efficacy tends to decrease as neuronal loss progresses. Neurotrophic factors (NTFs) are endogenous proteins known to promote neuronal survival, even in degenerating states. Therefore, the use of these factors is regarded as a possible therapeutic approach, which would aim to prevent PD or to even restore homeostasis in neurodegenerative disorders. Intriguingly, although favorable results in in vitro and in vivo models of the disease were attained, clinical trials using these molecules have failed to demonstrate a clear therapeutic benefit. Therefore, the development of animal models that more closely reproduce the mechanisms known to underlie PD-related neurodegeneration would be a major step towards improving the capacity to predict the clinical usefulness of a given NTF-based approach in the experimental setting. Moreover, some adjustments to the design of clinical trials ought to be considered, which include recruiting patients in the initial stages of the disease, improving the efficacy of the delivery methods, and combining synergetic NTFs or adding NTF-boosting drugs to the already available pharmacological approaches. Despite the drawbacks on the road to the use of NTFs as pharmacological tools for PD, very relevant achievements have been reached. In this article, we review the current status of the potential relevance of NTFs for treating PD, taking into consideration experimental evidence, human observational studies, and data from clinical trials.