While Knuth has declared that TeX will never change in any substantial way, there remain things that one might wish had been done differently, or indeed implemented at all.
The NTS project set out to produce an advanced replacement for TeX, to provide a basis for developing such modifications: this “New Typesetting System” would share Knuth’s aims, but would implement the work in a modern way taking account of the lessons learned with TeX. While a first demonstrator NTS did appear, it wasn’t practically useful, and the project seems no longer active.
In parallel with its work on NTS itself, the project developed a set of extensions that can be used with a (“true”) TeX system. Such a modified system is known as an e-TeX system, and the concept has proved widely successful. Indeed, current TeX distributions are delivered with most formats built with an e-TeX-based system (for those who don’t want them, e-TeX’s extensions can be disabled, leaving a functionally standard TeX system).
The extensions range from the seemingly simple (increasing the number of available registers from 256 to 32768) through to extremely subtle programming support.
CONTeXT has required e-TeX for its operation for some time, though development is now focused on the use of LuaTeX.
Some LaTeX packages already specify the use of e-TeX. Some such packages may not work at all on a non-e-TeX system; others will work, but not as well as on an e-TeX system. The LaTeX team has announced that future LaTeX packages (specifically those from the team, as opposed to those individually contributed) may require e-TeX for optimum performance.
This answer last edited: 2011-07-13