Apart from mutational activation of canonical HH/GLI signaling, several cancer entities with high medical need display noncanonical, SMO-independent mechanisms involving a number of prominent oncogenic players, e.g., RAS/MEK/ERK, PI3K/AKT, JAK/STAT, epigenetic modifiers or various members of distinct kinase families (for details, see below) that directly or indirectly impinge on and enhance GLI activity. This evidence concerns the gene SMO and cancer.