Stem cells use mode of cell division, symmetric (SCD) versus asymmetric (ACD), to balance expansion with self-renewal and the generation of daughter cells with different cell fates. Studies in model organisms have identified intrinsic mechanisms that govern this process, which involves partitioning molecular components between daughter cells, frequently through the regulation of the mitotic spindle. Research performed in vertebrate tissues is revealing both conservation of these intrinsic mechanisms and crucial roles for extrinsic cues in regulating the frequency of these divisions. Morphogens and positional cues, including planar cell polarity proteins and guidance molecules, regulate key signaling pathways required to organize cell/ECM contacts and spindle pole dynamics. Noncanonical WNT7A/VANGL2 signaling governs asymmetric cell division and the acquisition of cell fates through spindle pole orientation in satellite stem cells of regenerating muscle fibers. During cortical neurogenesis, the same pathway regulates glial cell fate determination by regulating spindle size, independent of its orientation. Sonic hedgehog (SHH) stimulates the symmetric expansion of cortical stem and cerebellar progenitor cells and contributes to cell fate acquisition in collaboration with Notch and Wnt signaling pathways. SLIT2 also contributes to stem cell homeostasis by restricting ACD frequency through the regulation of spindle orientation. The capacity to influence stem cells makes these secreted factors excellent targets for therapeutic strategies designed to enhance cell populations in degenerative disease or restrict cell proliferation in different types of cancers.