Cell-to-cell signaling molecules such as the Wnt proteins that directly influence the expression of cell-type specific transcriptional programs are essential for tissue generation in metazoans. The mechanisms supporting cellular responses to these molecules represent potential points of intervention for directing cell fate outcomes in therapeutic contexts. Small molecules that modulate Wnt-mediated cellular responses have proven to be powerful probes for Wnt protein function in diverse biological settings including cancer, development, and regeneration. Whereas efforts to develop these chemicals as therapeutic agents have dominated conversation, the unprecedented modes-of-action associated with these molecules and their implications for drug development deserve greater examination. In this review, we will discuss how medicinal chemistry efforts focused on first in class small molecules targeting two Wnt pathway components – the polytopic Porcupine (Porcn) acyltransferase and the cytoplasmic Tankyrase (Tnks) poly-ADP-ribosylases – have contributed to our understanding of the druggable genome and expanded the armamentarium of chemicals that can be used to influence cell fate decision-making.