Plasmodesmata (PD) link the cytoplasm of two adjacent cells, allowing intercellular trafficking of solutes, signaling molecules, protein, RNA and ribonucleoprotein complexes. The regulation of plasmodesmata-mediated trafficking is essential for plant growth and development. A hypothesis called Organelle-nucleus-plasmodesmata-signaling (ONPS) developed by our group posits that specific changes in organellar (plastids or mitochondria) state led to signaling to the nucleus (chloroplast-to-nucleus retrograde signaling, CRS) which tunes expression of nucleus-encoded genes associated with plasmodesmal regulation. Investigation of known signaling pathways involved in chloroplast-to-nucleus retrograde signaling suggests that these pathways are also involved in regulating plasmodesmata. We have analyzed intercellular trafficking in the Arabidopsis thaliana gun mutants and silenced GUN and other tetrapyrrole biosynthesis-related genes in Nicotiana benthamiana plants. Indeed, we have found that intermediates in the tetrapyrrole biosynthetic pathway may have an important role in ONPS. These studies reveal complexity in the cellular signaling mechanisms that regulate intercellular trafficking and illuminate the important roles of metabolites in signaling.