Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by a progressive decline in cognition and memory, leading to significant impairment in daily activities and ultimately death. It is the most common cause of dementia, the prevalence of which increases with age; however, age is not the only predisposing factor. The pathology of this cognitive impairing disease is still not completely understood, which has limited the development of valid therapeutic options. Recent years have witnessed a wide range of novel approaches to combat this disease, so that they greatly increased our understanding of the disease and of the unique drug development issues associated with this disease. In this paper, we provide a brief overview of the history, the clinical presentation and diagnosis, and we undertake a comprehensive review of the various approaches that have been brought to clinical trials in recent years, including immunotherapeutic approaches, tau-targeted strategies, neurotransmitter-based therapies, neurotropic and hematopoietic growth factors, and antioxidant therapies, trying to highlight the lessons learned from these approaches. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.