This special issue of JPR celebrates the fifth anniversary of the Chromosome-Centric Human Proteome Project (C-HPP). We present 27 manuscripts in four categories: (i) Metrics of Progress and Resources, (ii) Missing Protein Detection and Validation, (iii) Analytical Methods and Quality Assessment, and (iv) Protein Functions and Disease. We briefly introduce key messages from each paper, mostly from C-HPP teams and some from the Biology and Disease-driven HPP. From the first few months of the C-HPP NeXt-MP50 Missing Proteins Challenge, authors report 73 missing protein detections that meet the HPP guidelines using several novel approaches. Finally, we discuss future directions.