More than a third of the proteome of all cells resides in membranes (membranome) or is secreted across lipid bilayer membranes (secretome). Membrane proteins are essential in catalyzing solute transport, energy conversion, stimuli sensing and signal transduction, cell division and biosynthesis. Membrane proteins such as G-protein coupled receptors and ion channels make up about 30-50% of the top drug targets. Secretory proteins are essential molecules for cell-cell signaling, surface attachment, pathogenic toxicity and enzymatic scavenging. The elucidation of the mechanisms that allow the correct targeting of proteins to membranes and their subsequent crossing of the lipid bilayer (secretory proteins) or their integration into it and subsequent assembly (membrane proteins) is a central and fascinating biological question. Understanding protein trafficking will also help us understand debilitating diseases that result from defective protein targeting such as cystic fibrosis. Because of their biophysically challenging nature, the elucidation of atomic resolution structures and the subsequent understanding of the catalytic mechanism of membranome/secretome proteins is bound to remain a major challenge for modern molecular biology.