The spike architecture is one of the most important agronomic traits that influence grain yield in wheat (Triticum aestivum). In our recent study, we initially cloned a dominant allele TaCol-B5 on chromosome arm 7BL that increases the number of spikelets per spike. The gene was named TaCol-B5 to be more consistent with its orthologue (CONSTANS-like 5) in other plant species. After cloned, TaCol-B5 showed association with increases in the length of the spike, the number of grains per spike, and the number of spikes per plant. When overexpressed, TaCol-B5 was found to enhance field-based grain yield by 11.9%. The natural variation between the two alleles relied on a single-nucleotide polymorphism that resulted in a critical amino acid substitution, so that TaCol-B5 protein but not Tacol-B5 protein was phosphorylated by the serine/threonine protein kinase TaK4. Another critical finding in this study is that the TaCol-B5 allele for higher grain yield was cloned from CItr17600, which is a cultivar in CIMMYT, and this allele was found in ancestral emmer wheat but only 2% of an international modern wheat variety panel (1,657 accessions). We also reported that TaCol-B5 increased the number of grains per spike while not decreasing grain weight, demonstrating that the trade-off between three individual yield components could be broken in genetics. We published this work in Science (376: 180-183, 2022). Science magazine also published a perspective paper on our gene in the same issue (376: 133-134). The story on TaCol-B5 is not over yet but is just a starting point in a roadmap for molecular improvement of grain yield. We will discuss about how to utilize the rare genetic source in breeding lines with various genetic backgrounds, how to increase grain yield while optimizing the plant architecture, and how to identify downstream targets of TaCol-B5 to establish a genetic pathway leading to higher grain yield in wheat.