Coronary artery disease (CAD) is one of the leading causes of death in both men and women aged > 65 years. However, older patients have been underrepresented in clinical trials resulting in limited data about the effectiveness of different treatment strategies in this population. Furthermore, the atypical clinical presentations of CAD in elderly patients, often make diagnosis challenging and can lead to suboptimal implementation of treatment and secondary preventive measures by health care professionals. This chapter reviews clinical presentations and diagnosis consideration of CAD in the elderly. This review will also address clinical challenges that often arise when considering medication therapy and percutaneous coronary intervention (PCI) in the elderly, as well as cardiac rehabilitation in this population. To optimize the benefits of therapy in the elderly, providers should consider complex interplay of variables such as comorbidities, functional and socioeconomic status, side effects associated with multiple drug administration, and individual biological variability.