The endoplasmic reticulum (ER) is a membrane-bound organelle responsible for the synthesis, assembly and post-translational modification of proteins destined for the lysosomes, Golgi and for secretion. The processes which occur in the lumen of the ER are vital to the correct functioning of the cell, and mechanisms must exist to enable the cell to monitor events within the lumen of the ER. How the cell is able to do this is not known, but it would apparently require the passage of signals from the lumen of the ER to the cytosol, from where signals can be sent to, for example, the nucleus to effect changes in transcription. Here, it is suggested that the membrane of the ER may contain the components (i.e. receptors, kinases, etc.) required for transmembrane signalling in much the same way as the plasma membrane does. This hypothesis will be discussed in relation to known ER proteins which might act as signalling proteins.