Microenvironment-targeted therapies are emerging as possible complementary approaches to treat malignancies. However, progress is hindered by the complexity of the interactions between malignant cells and their microenvironment. In leukemia, this complexity is further emphasized by a highly dynamic behavior of leukemic cells recently reported in Nature. Hawkins et al.1 analyze leukemic cell localization relative to microenvironmental cells in T-cell acute lymphoblastic leukemia (T-ALL) through real-time intravital imaging. Contrasting previous studies, Lo Celso and colleagues report a highly motile behavior and lack of stable interactions with specific microenvironmental cell types during disease progression or after chemotherapy. This study challenges some current concepts on microenvironmental dependence of leukemia.