The upper stage was also used as an uncrewed orbital target vehicle for the Gemini crewed spacecraft to practice rendezvous and docking.

Late in 1960, Lockheed introduced the uprated Agena B stage which was restartable and had longer propellant tanks for more burn time.

The Atlas LV-3 Agena B was used between 1961 and 1965 for a variety of NASA and DoD programs, including Ranger, Mariner, Samos, and Midas but proved a unreliable, with only 21 successes in 28 flights.

In late 1962, after Ranger 5 suffered a booster malfunction, albeit a minor one that ground controllers were able to work around, NASA convened a review board which undertook a wholesale reevaluation of the Atlas-Agena as a launch vehicle.

The board found that quality control and checkout procedures were poor, and that this situation was exacerbated by the several dozen configurations of the booster, as each individual DoD and NASA program necessitated custom modifications to the Atlas and Agena, and the latter also differed in its Atlas and Thor variants.

The board recommended improved quality control, better hardware, and also establishing one standardized launch vehicle for all space programs.

The Agena D first flew in July 1963, starting a series of 15 successful launches for NASA and Air Force programs, including Ranger, Mariner, Midas, and Gambit.

Forty-seven Atlas SLV-3 Agena D boosters were flown over the following years, mostly for the KH-7 Gambit and Vela programs, and also for a few NASA missions like Mariner.

The Gemini-Agena Target Vehicle had a specially modified Range Safety destruct system designed to fire slugs into the propellant tanks rather than the conventional method of rupturing them externally, since an inadvertent activation in orbit could endanger the Gemini astronauts.

The very first Atlas-Agena flight, Midas 1 in February 1960, failed when the unproven ISDS system mistakenly activated at staging, rupturing the Atlas's LOX tank and causing the breakup of the Agena.

However, the Agena malfunctioned on both flights and left the probes trapped in a useless low Earth orbit from which they soon decayed.

Ranger 5 suffered an unknown failure which deprived it of power, and it missed the Moon by 725 kilometers (391 nautical miles).

It carried microwave and infrared radiometers, and sensors for cosmic dust, solar plasma and high-energy radiation, and magnetic fields.

All launches were successful, and a total of 99 percent of the surface of the Moon (near and far side) was mapped with resolution as high as 3 ft 3 in (1 meter).

The spacecraft also carried micrometeoroid sensors, which showed the average micro-meteoroid flux near the Moon to be two orders of magnitude greater than in interplanetary space, but slightly less than the near-Earth environment.

There were several failures, including an on-pad explosion of an Atlas, and the program was cancelled at the end of 1962 without ever demonstrating any operational capability.

Vela consisted of two sets of Air Force satellites flown in 1964–65 to monitor Soviet compliance with the Nuclear Test Ban Treaty on Atlas-Agena Ds.