Bitterness is a defining and intricate characteristic of coffee. This review offers a comprehensive analysis of the state-of-the-art techniques related to coffee bitterness research and summarizes known bitterants present in coffee, including phenolics, peptides, alkaloids, and diterpenoids. It also discusses critical factors that affect bitterness, such as coffee variety, ripeness, processing methods, roasting degrees, and brewing techniques, as well as individual human differences in taste perception. Notably, the potential for bitterness inhibition in coffee is also explored. In addressing the challenges faced in bitterness research, this review identifies gaps in the current knowledge and suggests future research directions, particularly in understanding the interactions among bitterants and their sensory implications. This review serves as a valuable resource for researchers seeking to deepen their understanding of the complexities of coffee bitterness.