The membrane protein Smoothened (SMO) is an oncogenic effector of Hedgehog (HH) signalling and is a drug target for cancers such as basal-cell carcinomas (BCCs), but resistance mutations in SMO have emerged. From a proteomics screen to search for additional HH pathway components as alternative drug targets, Atwood et al. found the polarity protein atypical protein kinase Cι/λ (aPKCι/λ), and they showed that it acts downstream of SMO in the activation of the GLI1 transcription factor. An inhibitor of aPKCι/λ suppressed both the growth of therapy-naive allografted BCCs in mice and also the proliferation of SMO-inhibitor-resistant BCC cells in vitro.