Sometimes, an overzealous quality control can cause systemic loss of function diseases preventing the transport of mutants that are nonetheless active. Unless promptly degraded, moreover, these can condense in ESC and cause gain of function diseases. Secretory IgM are complex polymers whose biogenesis occurs stepwise in ESC. Like other unassembled Ig-H chains, secretory m interact with BiP via their first constant domain. Assembly with Ig-L displaces BiP, and m2L2 complexes are then slowly polymerized. When CH1 is lacking, mDCH1 accumulate in a detergent insoluble form within dilated ESC cisternae, also called Russell Bodies Wortmannin providing a suitable model system for Heavy Chain Disease and ER storage disorders. We recently identified some of the factors that modulate mDCH1 condensation in living cells. For instance, over-expression of ERp44, a multifunctional chaperone that mediates thiol-dependent quality control of IgM subunits and other clients, stimulated the accumulation of mDCH1 in RB. To learn more about how cells handle different proteins in ESC, we generated different chimeric proteins containing a Halotag derived from a Rhodococcus rhodochrous Haloalkane dehalogenase whose active site has been engineered to covalently bind fluorescently-labelled chloro-alkane derivatives. With respect to more conventional live-cell labelling based on fluorescent proteins the Halotag post-translational labelling system has several advantages. First, it allows to using organic dyes such as TMR or R110, that are brighter and more photostable than fluorescent proteins and whose fluorescence is relatively pH-insensitive. By selecting suitable ligands the same tag can be used for live cell microscopy, immunofluorescence, Western Blotting, protein purification and co-precipitation assays. Moreover, the Halotag allows following the accumulation and/or the degradation of the protein of interest by two-color pulse/chase experiments with high temporal resolution. Lastly, the Halotag has the advantage of not possessing glycosylation sites, that could affect folding and transport of the chimeric proteins in the secretory compartment. Another hybrid system, based on small molecules able to covalently bind genetically specified proteins, is the tetracysteine biarsenical system. Unfortunately, due to the oxidative environment of the ER, this system cannot be applied to the study of secretory proteins. In this work, after confirming that Halo folds and maintains its activity in ESC without grossly perturbing the fate of the target protein, we followed the condensation of Halo-mDCH1 in ESC and analysed the growth and mobility of the resulting RB in vivo exploiting the property of covalently binding ligands coupled to different fluorochromes. Moreover, by appending the Halotag to short- and long-lived ER residents and to transport competent molecules, we show that it is possible to follow protein degradation and secretion bypassing classic radioactive pulse and chase techniques. Thus, Halo is a versatile non-invasive tool to follow key events in the secretory pathway. The standard approach to study protein degradation is based on radioactive pulse and chase experiments, limited by the restrictions of using radioactive isotopes.