Osteonecrosis (ON) represents one of the most common and debilitating sequelae of antileukemic treatment in children and adolescents with acute lymphoblastic leukemia (ALL). Systematic screening strategies can focus on early detection and intervention to prevent ON from progressing to stages associated with pain and functional impairment. These strategies hold promise for reducing ON-associated morbidity without the risk of impairing leukemia control. Herein, we critically reviewed clinical data on pharmacological, nonpharmacological/nonsurgical, and surgical (including cellular) treatment options for ON, which are covered in the literature and/or are conceivable based on the supposed underlying ON pathophysiology. Prevention of ON progression is of paramount importance, and attempts seem to be more effective in early (precollapse) disease status than in late-stage (collapse) ON. Based on the results of ongoing prospective magnetic resonance imaging screening studies, which will hopefully identify those patients with a high risk of ON progression and debilitating sequelae, prospective interventional studies are urgently needed. Although there is still a lack of high-quality studies, based on currently available data, core decompression surgery combined with cellular therapies (eg, employing mesenchymal stem cells) appears most promising for preventing joint infraction in children at high risk of developing late-stage ON.