I’m surprised I haven’t seen anything about this anywhere else. When multiple screens are connected together, you lose one (or two) of the most important features of a single window: the right and left edges. As Bruce Tognazzini mentions in his timeless article on Fitts’ Law, the edges are very fast for user access. This is one reason that Apple’s menu bar (across the top) is so much better than the way Sun and Microsoft and others have done it: see point 5 in Tog’s article.
There is also an absolutely wonderful writeup of Fitt’s Law by Kevin Hale titled Visualizing Fitts’ Law – with a presentation with excellent visualizations and examples. Jensen Harris also wrote an article on Fitts’ Law: of particular note are the examples of how Fitts’ Law affected the design of Microsoft Windows and Microsoft Office.
In Tog’s article on Fitts’ Law, he describes how he experimented with “multiple desktops” (though at the time, it may have seemed more arbitrary than that). With a second monitor on top of the first, and a menu that users could “bypass” into the top monitor, it actually slowed the user down quite considerably: at first, the menu was missed quite often until the user slowed way down to get at the menu.
When using multiple monitors in a horizontal direction (a typical layout) the right edge of the left screen and the left edge of the right screen become very hard to hit. This especially becomes a problem with programs that are maximized. Consider the example of a typical scrollbar (normally on the right hand side) on a maximized application on one of the two monitors. On the left-side monitor, it becomes a hard target as the user has to directly aim and slow down to hit it. If on the right-side monitor, the scroll bar essentially becomes infinitely large and can be hit without any trouble at all.
Using multiple monitors also completely eradicates two of the five easiest locations to reach: two corners are no longer easily “reachable” – or perhaps reachable at all. This easy reachability of the corner is perhaps one reason that programs put the window control buttons in the top right corner; with another monitor on the right the corner becomes that much harder to hit. If there is a monitor above, then it becomes just that much harder.
When using multiple monitors on on system tied together, the possibilities of rectifying this usability problem is only available to the extent that the operating system allows it. However, if you use synergy to tie multiple computer displays together, there is at least, several ways to regain the “infinitely large” target of a screen edge.
One is to use the “lockCursorToScreen” capability of Synergy. Synergy uses the ScrollLock key to do this by default. You can also use a hot key – this display is from the Synergy+ server for Windows:

Hot Keys are set at startup, accessable via the Hot Keys button. With a mouse and window “locked” with this option, you get back your right and left edges, and they once again behave the way operating system designers expected. With the toggle, you can go back and forth. There is, however, no way to discern whether the screen is locked or not, aside from the fact that the ScrollLock key setting is often visible on the keyboard: this is a usability failing in this feature.
Using the “double-tap” or “time delay” features of Synergy (with respect to switching displays) turns out to be extremely frustrating for the user, switching at times that are unexpected and not switching when desired.
Another possibility would be to not link the multiple displays together at all, and use key commands to switch between screens. This, however, may be more trouble than it is worth; I’ve not tried it and it does not seem possible to configure Synergy+ this way from the configuration screens.