A big surprise in the molecular cell biology of eukaryotes has been the discovery of pathways of protein secretion that are not linked to the endoplasmic reticulum (ER) and the Golgi apparatus. Various kinds of unconventional secretory processes have been described, including two major pathways for two distinct sets of cargoes that are initially synthesized as soluble proteins in the cytoplasm. These two pathways are mechanistically distinct from one another. One is based upon direct protein translocation across lipidic pores in the plasma membrane (type I unconventional secretion). The second pathway involves the recruitment of cytoplasmic proteins into vesicular compartments of the endocytic membrane system that fuse with the plasma membrane to release proteins into the extracellular space (type III unconventional secretion). This primer highlights the mechanisms and molecular machineries of these pathways that were discovered with fibroblast growth factor 2 (FGF2; type I) and acyl-CoA binding protein (Acb1; type III) as the most prominent cargo proteins. Furthermore, the physiological significance of these secretory routes in both health and disease is discussed for a broader range of cargo proteins.