In acute ischemic stroke, time is brain. Current guidelines recommend that the time from arrival at hospital to initiation of administration of tissue plasminogen activator, also known as the door-to-needle (DTN) time, should be 60 min or less. However, DTN times in practice usually exceed this recommended time. The median DTN times from the American Heart Association/American Stroke Association Get With The Guidelines-Stroke program and the multinational Safe Implementation of Treatment in Stroke International Stroke Thrombolysis Register are 75 min and 65 min, respectively. Prehospital factors associated with delays include patient-related factors such as poor recognition of stroke symptoms, poor use of emergency medical services, and complex psychosocial factors. Accurate recognition of stroke symptoms at a dispatcher and paramedic level is associated with shorter onset-to-arrival times. Prenotification of regional stroke centers by paramedics is strongly associated with shorter DTN times. In-hospital delays resulting in prolonged DTN times can be attenuated by having well-defined rapid triage pathways, defined stroke teams, single-call stroke team activation, established code stroke protocols, rapid access to diagnostic imaging, and laboratory services. In this review we summarize factors associated with prolonged DTN times and processes that allow faster onset-to-treatment times. Recent developments in the field are highlighted.