Abstract One of the challenges of incorporating molecularly targeted drugs into multi‐agent chemotherapy (backbone) regimens is defining dose‐limiting toxicities (DLTs) of the targeted agent against the background of toxicities of the backbone regimen. An international panel of 22 pediatric acute lymphocytic leukemia (ALL) experts addressed this issue ( www.ALLNA.org ). Two major questions surrounding DLT assessment were explored: (1) how toxicities can be best defined, assessed, and attributed; and (2) how effective dosing of new agents incorporated into multi‐agent ALL clinical trials can be safely established in the face of disease‐ and therapy‐related systemic toxicities. The consensus DLT definition incorporates tolerance of resolving Grade 3 and some resolving Grade 4 toxicities with stringent safety monitoring. This functional DLT definition is being tested in two Children's Oncology Group (COG) ALL clinical trials. Pediatr Blood Cancer 2010;54:872–878 © 2010 Wiley‐Liss, Inc.