It was designed for use in revolvers, but was soon chambered in rifles as well, in which it gained a reputation as a small game cartridge.

Many firearms designed for the .22 long rifle will chamber and fire the shorter round, though the .22 long generally does not generate sufficient energy to operate semi-automatic guns.

The large barrel volume to chamber volume ratio of a .22 rimfire rifle means that the powder gasses have expanded as far as they can before the bullet reaches the muzzle of a normal-length rifle barrel, and the light .22 long bullet has less inertia than the .22 long rifle.

The quieter report and lower penetration of the .22 long cartridge were often seen as desirable qualities.

Modern Hypervelocity loadings of the .22 long rifle use bullets as light as 30 gr (1.9 g), and modern blends of powder to generate velocities higher than normal loads, and chamber pressures high enough to cycle semi-automatic firearms reliably.