Understanding the complex relationships among cells and signaling molecules that underlie tissue organization is challenging, and developmental niches have been difficult to define concretely. Now Calderón and Boehm have capitalized on the fact that a single transcription factor (forkhead transcription factor, Foxn1) directs the differentiation of the thymus to create an experimental system for unraveling differentiation states. Using nude mice (homozygous deleted for Foxn1), which have a rudimentary thymus, the researchers engineer the thymus in vivo by adding back four factors previously identified as important to T-cell development—chemokines Ccl25 and Cxcl12, the cytokine Scf (stem cell factor) and the Notch ligand DLL4. In animals, expressing each separately or together in various combinations, thymus glands are populated with different members of the hematopoietic family: Ccl25 alone draws lymphoid cells to an otherwise empty thymus, Cxcl12 brings in B-cell progenitors, Scf increases myeloid progenitor cells and DDL alone does nothing but in combination over-rides the other factors in inducing T-cell differentiation. The researchers found that the factors acted synergistically—two factors together increased the numbers of progenitor cells—and in a context-dependent fashion—alone, Cxcl12 supports B-cell progenitors, but with DLL4, T-cell progenitors predominate. Synthetic environments may prove useful in unraveling the complex relationships within microenvironments that determine cell fate. (Cell 149, 159–172, 2012)