The AS/400 is a continuation of the System/38 database machine architecture (announced by IBM in October 1978 and delivered in August 1979). The AS/400 added source compatibility with the System/36 combining the two primary computers manufactured by the IBM Rochester plant. The System/36 had been IBMs most successful mini-computer but the architecture had reached its limit. The first AS/400 systems were delivered in 1988, and the product line has been refreshed continually since then.

The AS/400 was the first general-purpose computer system to attain a C2 security rating from the NSA, and in 1995 was extended to employ a 64-bit processor and operating system.

In 2000 IBM renamed the AS/400 to iSeries, as part of its e-Server branding initiative. The product line was further extended in 2004 with the introduction of the i5 servers, the first to use the IBM POWER5 processor. The architecture of the system allows for future implementation of 128-bit processors when they become available. Existing programs will use the new hardware without modification.

Although announced in 1988, the AS/400 remains IBM's most recent major architectural shift that was developed wholly internally. Since the arrival of Lou Gerstner in 1993, IBM has viewed such colossal internal developments as too risky. Instead, IBM now prefers to make key product strides through acquisition and to support the development of open standards, particularly Linux. It is noteworthy that after the departure of CEO John Akers in 1993, when IBM looked likely to be split up, Bill Gates commented that the only part of IBM that Microsoft would be interested in was the AS/400 division. (At the time, many of Microsoft's internal systems ran on the AS/400 platform