After 1939 with the beginning of the Second World War, concentration camps increasingly became places where the enemies of the Nazis were killed, enslaved, starved, and tortured. During the War concentration camps for “undesirables" spread throughout Europe. New camps were created near centers of dense "undesirable" populations, often focusing on areas with large communities of Jewish, Polish intelligentsia, Communists, or Roma. Most camps were located in the area of General Government in occupied Poland for a simple logistical reason: millions of Jews lived in Poland. It also allowed the Nazis to transport the German Jews outside of the German main territory. In most camps, prisoners were forced to wear identifying overalls with colored badges according to their categorization: red triangles for Communists and other political prisoners, green triangles for common criminals, pink for homosexuals men, purple for Jehovah's Witnesses, black for Gypsies and asocials, and yellow for Jews.

Sometimes the concentration camps were used to hold important prisoners, such as the generals involved in the attempted assassination of Hitler; U-Boat Captain-turned Lutheran pastor Martin Niemöller; and Admiral Wilelm Canaris, who was interned at Flossenbürg on February 7, 1945, until he was hanged on April 9, shortly before the war’s end.

In the early spring of 1941 the SS, along with doctors and officials of the T-4 Euthanasia Program, began killing selected concentration camp prisoners in Operation 14f13. The Inspectorate of the Concentration Camps categorized all files dealing with the death of prisoners as 14f, and those of prisoners sent to the T-4 gas chambers as 14f13. Under the language regulations of the SS, selected prisoners were designated for special treatment. Prisoners were officially selected based on their medical condition; namely, those permanently unfit for labor due to illness. Unofficially, racial and eugenic criteria were used: Jews, the handicapped, and those with criminal or antisocial records were selected. For Jewish prisoners there was not even the pretense of a medical examination: the arrest record was listed as a physician’s diagnosis. In early 1943, as the need for labor increased and the gas chambers at Auschwitz became operational, Heinrich Himmler ordered the end of Operation 14f13.

After 1942, many small subcamps were set up near factories to provide forced labor. IG Farben established a synthetic rubber plant in 1942 at Auschwitz III (Monowitz), and other camps were set up next to airplane factories, coal mines, and rochet fuel plants. Conditions were brutal, and prisoners were often sent to the gas chambers or killed if they did not work fast enough.

After much consideration, the final fate of the Jewish prisoners was announced in 1942 at the Wannsee Conference to high ranking officials.

Near the end of the war, the camps became sites for horrific medical experiments. Eugenics experiments, freezing prisoners to determine how exposure affected pilots, and experimental and lethal medicines were all tried at various camps.

Female prisoners were routinely raped and degraded in the camps.

The camps were liberated by the Allies between 1943 and 1945, often too late to save the prisoners remaining. For example, when the UK entered Bergen-Belsen concentration camp in 1945, 60,000 prisoners were found alive, but 10,000 died within a week of liberation due to typhus and malnutrition.

The British intelligence service had information about the concentration camps, and in 1942 Jan Karski delivered a thorough eyewitness account to the government.