G protein-coupled receptors (GPCRs) constitute the largest family of human membrane proteins. GPCRs recognize diverse extracellular stimuli and activate intracellular signaling cascades that regulate key physiological processes such as neurotransmission and cardiovascular function. The controlled transport of nascent GPCRs from the endoplasmic reticulum (ER) via the Golgi apparatus to the cell surface critically determines the cellular responsiveness to incoming ligands. Here, we present a comprehensive overview of the cellular mechanisms and motif-driven interactions with regulatory proteins that orchestrate GPCR folding, post-translational modifications, and vesicular transport along the secretory pathway. We highlight signaling cues that can modulate the anterograde transport and specialized mechanisms that deliver biosynthetic GPCRs to dendrites and axons in neurons. Furthermore, we discuss that many disease-causing GPCR mutants exhibit aberrant intracellular retention, which can be rescued by pharmacological strategies that stabilize misfolded GPCRs. Finally, we highlight insights into the agonist-driven signaling of biosynthetic GPCRs in secretory organelles. This review covers the complex roles of anterograde transport in controlling GPCR function and emerging possibilities to target the underlying mechanisms in disease.