When critically ill, a severe weakness of the limbs and respiratory muscles often develops with a prolonged stay in the intensive care unit (ICU), a condition vaguely termed intensive care unit-acquired weakness (ICUAW). Many of these patients have serious nerve and muscle injury. This syndrome is most often seen in surviving critically ill patients with sepsis or extensive inflammatory response which results in increased duration of mechanical ventilation and hospital length of stay. ⋯ In this chapter we discuss the current knowledge on the pathophysiology and risk factors of ICUAW. Tools to diagnose ICUAW, how to separate ICUAW from other disorders, and which possible treatment strategies can be employed are also described. ICUAW is finally receiving the attention it deserves and the expectation is that it can be better understood and prevented.