Phage display has proven to be a highly effective method of generating specific binding molecules that are used to build protein-based therapeutics. However, there is still a need for better phage display libraries, and ways to overcome the challenges that the immunized-sourced libraries provide. Here, we show a real-life example of a successful fully human synthetic sdAb phage display library. We also comment on the challenges currently faced and how to overcome them. Our approach involves many parameters such as library QC, specific panning outputs, efficient transition to mammalian expression, and what to look for in the resulting candidates. These VHO candidates show great promise in moving through late discovery phase and onto the generation of protein-based therapeutics.