There are two major flavors of Linux distros out there. Debian and Red Hat based distributions account for a large percentage of the distributions out there.
The major difference between them is the package management. If they are Debian based, they most likely use the dpkg& apt/deb system; if it's a Red Hat system, it most likely uses yum/rpm. A lot of distros pop up because someone was unsatisfied with the package management, so most will have some form of graphical interface that is different, but the underlying system is the same.
If you learn how to use apt-get and yum, you'll cover 80% of the distros out there, and 99% of the systems you'll most likely encounter.
Each distro will do something a little different with the window manager. Most major distros choose between KDE and Gnome, with Gnome seeming to be the popular one at the moment. The great thing about Linux though, is that you can change the window manager if you like (go Window Maker!).
If you learn the command line, there is not "much" of a difference, but the GUI changes between distros will definitely sway your choice. Also, some distros ship with drivers that will make it easy for certain hardware like video cards.
I highly recommend Linux Mint for home systems, and vanilla Debian, Ubuntu (server edition), or CentOS for servers.