Schematic representation of proposed mechanisms underlying CNS infiltration and subsequent relapse. In model 1, only some leukemic cells acquire the ability to enter the CNS, and the risk of CNS relapse depends on the presence or absence of a clone (shown in green) with the capacity to leave the BM and enter the CNS. Different leukemia subtypes may vary in this capacity, with some (shown as blue) unable to enter the CNS compartment, others avidly trafficking to the CNS (shown as green), and some acquiring this capacity in rare subclones (shown as mixed purple, blue, and green). In model 2, all leukemic cells may have the ability to seed this compartment, and subclinical CNS involvement at diagnosis may be universal and show little or no subclonal selection. In both cases, CNS relapse may also be determined by whether cells can adapt to the foreign microenvironment of the CNS and evade elimination by ALL-directed therapy and/or immunologic surveillance (in this example, green and/or yellow subclones have been selected for at relapse).