You're typing or keying too long without a break.
Overuse can lead to pain - this frequently occurs after you've been keying too fast or for too long without a break. Make sure to take frequent "mini-breaks - these can be as short as 15-30 seconds. Also, consider stretching during this period. See Stretches and Exercises.
You're gripping your pencil or pointing device too tightly.
Try using a lighter grasp or an ergonomic pen (these pens have wider bases that are easier to grip) or buying a rubber grip for your pen. See Mouse Setup and Usage.
There's pressure on your wrist or palms.
Avoid using soft or curved wrist rests. If you have a flat wrist rest, make sure that you don't rest the crease of your wrist on this, especially when typing or mousing. Use this to rest the palm of your hands in between typing and mousing work. See Keyboard Setup and Usage.
You're operating a trackball with only your thumb.
Even our thumbs can get tired if used enough. Try alternating the fingers you use to operate the trackball and try to keep your hands as flat as possible.
You're extensively clicking your mouse.
Excessively clicking a standard mouse can lead to discomfort in your fingers (particularly your index finger). Consider a trackball or a mouse with a "clicker" that is thumb-activated.
You're typing extensively at a 10-key pad or calculator.
People who use the 10-key pad extensively - accountants, payroll personnel, and others - often experience discomfort after working for extended periods. Using a detachable 10-key pad may free you from the keyboard and let you rest your hand in a more comfortable position. Also, consider using your other hand (known as "load sharing") to operate the keypad. Though it may seem strange at first, most people get used to the change in just a few days.