While the Delta IV retains the name of the Delta family of rockets, major changes were incorporated. Perhaps the most significant change was the switch from kerosene to liquid hydrogen fuel, with new tankage and a new engine required.

The Delta IV Medium (Delta 9040) was the most basic Delta IV. It featured a single CBC and a modified Delta III second stage, with 4-meter liquid hydrogen and liquid oxygen tanks (called a Delta Cryogenic Second Stage (DCSS)) and a 4-meter payload fairing.

The Delta IV Medium+ (4,2) (Delta 9240) had the same CBC and DCSS as the Medium, but with the addition of two 1.5-m (60-in) diameter solid rocket booster Graphite-Epoxy Motors (GEM-60s) strap-on boosters.

The Delta IV Medium+ (5,2) (Delta 9250) was similar to the Medium+ (4,2), but had a 5-m–diameter DCSS and payload fairing for larger payloads.

The Delta IV Medium+ (5,4) (Delta 9450) was similar to the Medium+ (5,2), but used four GEM-60s instead of two.