The C1q-globular domain (gC1qD) is a highly conserved oligomerization motif that distinguishes a superfamily of proteins, which includes circulating factors like C1q (the first component of the complement cascade) and adiponectin. The compact structure resulting from gC1qD trimerization is well known for its versatility in establishing highly specific interactions with different ligands. Among the many binding targets are a large number of extracellular membrane-associated receptors involved in cell development, apoptosis, and immunological processes. Interestingly, proteins interacting with the prototypical globular domain of C1q have been described also inside the cell where they were shown to recognize signal transducers such as G protein coupled receptors and their downstream effectors. Afterward, it was shown that variants of the gC1qD have been adopted by intracellular proteins involved in signal transduction. This review summarizes the evidence supporting the presence of the gC1qD inside the cell and explores the possibility that the domain might play novel signaling functions in this context, such as determining highly specific protein-protein interactions aimed to organize signaling complexes on the cytosolic side of cellular membranes.