Schematic representation of canonical and noncanonical Hh signaling activation in MM. The signaling is triggered by binding of ligand, produced by Hh signaling cells, such as MM cells or BMSCs, to Ptch1 on target cells (canonical or ligand-dependent/ receptor-induced signaling). This leads to inhibition of Ptch1 via cellular internalization and Smo localization on the cell surface. Smo activation leads to nuclear translocation of Gli transcription factors followed by expression of Gli target genes, such as c-myc, cyclin-D1, and Bcl-2. The biologic effect is cell proliferation, with deregulation contributing to tumorigenesis. Abnormal Hh pathway activation occurs also by the mechanisms of activation downstream to Smo (noncanonical or ligand-independent Hh signaling). Genetic alterations or ciliary protein overexpression leading to functional redundancy of Gli transcription factors, crosstalk between Hh signaling, and unrelated pathway are all causes of noncanonical Hh signaling activation. Canonical and noncanonical Hh pathways probably work in parallel, and a multitargeted approach directed against Hh signaling may be a more effective therapeutic strategy.