B cell acute lymphoblastic leukemia (B-ALL) arises from genetic alterations impacting B cell progenitors, ultimately leading to clinically overt disease. Extensive collaborative efforts in basic and clinical research have significantly improved patient prognoses. Nevertheless, a subset of patients demonstrate resistance to conventional chemotherapeutic approaches and emerging immunotherapeutic interventions. This review highlights the mechanistic underpinnings governing B-ALL transformation. Beginning with exploring normative B cell lymphopoiesis, we delineate the influence of recurrent germline and somatic genetic aberrations on the perturbation of B cell progenitor differentiation and protumorigenic signaling, thereby facilitating the neoplastic transformation underlying B-ALL progression. Additionally, we highlight recent advances in the multifaceted landscape of B-ALL, encompassing metabolic reprogramming, microbiome influences, inflammation, and the discernible impact of socioeconomic and racial disparities on B-ALL transformation and patient survival.