Background: Causes of ischemic stroke in young adults (15–45 years) are diverse, but undetermined etiology is common in a majority of studies. Aims: The present series study aims to evaluate causes and changes in the etiological diagnosis of ischemic stroke in young adult patients admitted to a tertiary medical center over a period of 27 years. Methods: We retrospectively reviewed the records of patients with a first-ever stroke in the age range of 15–45 years who were admitted to the ‘12 de Octubre’ University Hospital between 1974 and 2002. Results: 272 young adults with ischemic stroke were identified. The etiological diagnoses were: undetermined in 36% of patients, large-artery atherosclerosis in 21%, cardioembolism in 17%, non-atherosclerotic vasculopathy in 17%, and other specific etiologies in 9%. While in the first study period (1974–1988) 45% of patients were diagnosed with uncertain etiology, in the last period (1989–2002) only 26% were diagnosed with cryptogenic stroke (45% with two or more potential etiologies identified; 45% with no identified cause despite complete evaluation, and 10% with incomplete evaluation). Conclusions: The etiological diagnosis of stroke in young adults has changed over time as a result of improvements in diagnostic workup. While cryptogenic stroke was the most frequent diagnosis in the past, today specific causes (non-atherosclerotic vasculopathy, large-artery atherosclerosis, cardioembolism and hematological disorder) are identified in the majority of patients.