Plasma cells, like other "professional" secretory cells, are capable of secreting thousands of proteins per second. To accomplish this impressive task, they contain a highly developed endoplasmic reticulum (ER), where newly synthesized proteins must fold and assemble to native structures before secretion. Protein biogenesis in the ER is coupled to a tight quality control schedule: aberrant molecules produced upon failure of the folding/oligomerization processes are retained in the ER, and eventually degraded by ER-associated degradation (ERAD) pathways. The activity of the ERAD machinery therefore needs to be adapted to variations in the load of the ER with cargo proteins. If ERAD is insufficient, misfolded proteins accumulate causing ER stress, apoptosis, and ER storage diseases. The capacity of ERAD also critically determines the efficiency of protein secretion. Here we summarize recent findings highlighting the role of ERAD in disease and development, particularly in professional secretory cells.