Toll-like receptors (TLRs) are well known activators of immune responses, but their involvement in the plasma cell (PC) differentiation process remains mostly unknown. This review is focused on the expression and function of TLRs on normal PCs and their malignant counterpart, Multiple Myeloma cells. We report studies that suggest a role for TLR ligands as adjuvants of the humoral immune response through the survival of newly generated immature PCs. On the contrary, TLRs do not seem to be involved in the long-term maintenance of PCs in the bone marrow. Multiple Myeloma cells express a broad range of TLRs, and show heterogeneous responses to different ligands. These double-edged-sword effects are presented and discussed in the context of tumor progression, and as putative therapeutic targets.