In the United States in 2005, there were 1,189 fatal crashes and 35,000 injurious crashes into guardrails. Current efforts to reduce fatalities occurring in guardrail collisions have focused on frontal oblique collisions of cars and light trucks into guardrail. These crashes however represent a diminishing target population for fatality reduction. This paper examines the current opportunities for reducing fatalities in guardrail collisions in the United States. The analysis was based upon crash data from the Fatality Analysis Reporting System (FARS) and the National Automotive Sampling System General Estimates System (GES) for the years 2000-2005. The greatest opportunity for fatality reduction is the protection of motorcyclists, who now account for 32% of guardrail fatalities, and car and light truck occupants in side impact, who now comprise 14% of all guardrail fatalities. Together, protection of motorcycle riders and protection of car and light truck occupants in side impacts account for nearly half of all fatalities (46%) which occur in vehicle-guardrail collisions. Additional targets for fatality reduction include light truck rollover and collisions with guardrail ends.