Regeneration of the tendon/ligament-to-bone interface (enthesis) is still a formidable clinical challenge due to the structural and mechanical complexity of the interface. Current clinical approaches using sutures and anchors to treat tendon/ligament tears from the insertion site result in high retear rates. The limited understanding of enthesis biology impedes the progress of functional and integrative regeneration. Mimicking the natural structure and mechanics of the enthesis remains a great difficulty to be solved. This review starts with describing the current clinical approaches with unsatisfactory outcomes, followed by the advances in biology highlighting the importance of enthesis development and maturation for inspiring new treatment options. Next, the biomimetic strategies based on current knowledge of the structural and mechanical properties of the enthesis are critically reviewed. Five sections are discussed in this part: the biomimetic design using the diverse extracellular matrix, the different levels of mineralization encapsulating in the biomaterials to mimic the enthesis, recapitulating different cell types of this interface region, mimicking the collagen fiber orientation at the enthesis, and promoting in situ stem cell differentiation and regeneration using various growth factors and metallic ions. Finally, we summarize the unmet needs and current obstacles in the effective regeneration of enthesis and highlight the trend for biomimetic design in the field.