Stem cells are highly specialized cells endowed with unlimited replicative self-renewing potential. These cells are capable of either limited multipotent (adult stem cells, ASC) or unlimited pluripotent (embryonic stem cells, ESC) differentiation to somatic cell lineages. Control of this differentiation process holds great promise in areas such as tissue regeneration and the treatment of chronic degenerative diseases. The medical exploitation of this phenomenon is carried out using stem cells derived from different sources (e.g., ASC/ESC), developmental stages (e.g., mesenchymal cells), cellular reprogramming (e.g., induced pluripotent stem cells), or even nonstem cells in a process known as transdifferentiation (Fig. 1). Despite this wide diversity, all of the differentiation steps that drive these cells to the desired somatic cell lineage rely on the directed manipulation of endogenous pathways. This process is achieved primarily by direct ligand signaling to cell-surface receptors, or use of distinct combinations of transcription factors derived from these signals. Now in PNAS, Melidoni et al. (1), building upon earlier reports (2, 3), raise the exciting possibility of using combinatorial library-derived antibodies intimately linked to stem-cell phenotype as a powerful tool in controlling these differentiation events.