Secretory and endocytic pathways of mammalian cells. CD40 molecules synthesized in the ER are delivered to the cell surface via the trans-Golgi network and vesicles that subsequently fuse with the plasma membrane. Some CD40 mutants carrying missense mutations or small in-frame deletions cannot complete this pathway but are retained instead in the ER. The 3 novel CD40 mutants identified by Lanzi et al in this issue exhibit distinct fates in the ER: (1) the P4 mutant does not leave the ER and is promptly degraded by ERAD; (2) the P2 mutant CD40 persists in the ER and activates UPR as determined by increased HSP production and XBP-1 splicing; and (3) the P5 mutant accumulates in the ER but neither is degraded nor elicits UPR. The P5 CD40 mutant is a candidate for therapies based on pharmacologic chaperones. (Professional illustration by Kenneth X. Probst.)