The prevention and treatment of progressing stroke should be one of the main therapeutic targets of neuroprotective therapies. Despite the high prevalence of progressing stroke in acute stroke (25–35%) and its importance as a predictor of poor outcome, no treatment capable of preventing early neurological deterioration (END) or of reducing its impact has yet been developed. It is essential that our understanding of END’s underlying mechanisms be improved as it is currently not possible to predict its occurrence accurately. Published studies to date have been unable to identify a clinical profile which reliably predicts those patients likely to suffer neurological deterioration in the very early acute phase of ischemic stroke. In the following pages, we will discuss the present situation with regard to neurological worsening in general, paying special attention to END given the prognostic and therapeutic implications of this common condition. Factors associated with neurological deterioration and the potential mechanisms, particularly excitotoxic theory, are discussed.