You can almost always make at least a little more room in your packs, like when you're trying to waddle back to town after cleaning out a Dungeon. The easiest thing to do is to mix up some Potions. Wear all the jewelry you can regardless of Enchantments. Carry your largest Shields and wear your bulkiest Armor. A character who normally fights with one type of weapon might be able to carry a bigger one instead, like arming a Necromancer with a Staff instead of a Dagger.
When you can't wear or pack anything else, you can always carry one more thing in front of you on the tip of the mouse arrow. Just make it the largest Item of all and pick it up last. You can cross between areas safely this way, and you can talk to characters outside and behind doors, but drop your cargo outside before dealing with shops and traders. You'll be able to retrieve it when you exit.