On January 19, 1943, the Germans began their second deportation of the Jews, which led to the first instance of armed insurgency within the ghetto. While Jewish families hid in their "bunkers," Germans and the Jewish Combat Organization(Żydowska Organizacja Bojowa, ŻOB) fighters engaged in two direct clashes. As a consequence, even as the ŻOB suffered severe losses (among them Yitzhak Gitterman), the deportation was halted within a few days, and only 5,000 Jews were removed instead of the 8,000 as planned by Globocnik.

Two resistance organizations, the Jewish Military Union (Żydowski Związek Wojskowy, ŻZW) and the ŻOB took control of the Ghetto. They built dozens of fighting posts and executed Jews whom they considered to be Nazi collaborators, including Jewish Police officers and Gestapo agents. The ŻOB established a prison to hold and execute traitors and collaborators. Józef Szerynski, the former head of the Jewish Police, committed suicide.

Ghetto fighters were armed, if at all, mostly with only pistols and revolvers of a limited value in combat with just a few  rifles and automatic firearms available. The insurgents had little ammunition, and relied heavily on improvised explosive devices and incendiary bottles. Some more weapons were supplied throughout the uprising or captured from the Germans. In his report of May 24, 1943, Stroop claimed to have captured a total of "seven Polish rifles, one Russian and one German rifle, 59 pistols of various calibers, several hundred incendiary bottles, home-made explosives, infernal machines with fuses, a large amount of explosives and ammunition for weapons of all calibers, including some machine gun ammunition" (adding that his forces were able to recover only a small part of the insurgent weapons)...