With respect to the total cure failure of current drugs used in the treatment of neurodegenemtive dis- eases, alternative strategies are followed. Particularly, neuroprotection approaches are questioned. Metal chelation, antioxidant towards oxidative stress, modulation of the amyloidogenic pathway, MAO-B inhibition, and NMDA receptor antagonism is more or less typical examples. Some of the representative drug candidates with promising neuroprotective features are assessed in clinical trials. Although initial attempts were found hopeful, none of the candidates have been found successful in each required clinical trials, particularly depending on the failures in terms of cognitive enhancement and slowing the progressive characteristics of neurodegenerative diseases. Today, neuropmtection is evaluated using multi-target ligand-based drug design studies. Within this study, the clinical outcomes of these studies, the rationale behind the design of the molecules are reviewed concomitant to the representative drug candidates of each group.