Difficult malocclusions are inevitable in every orthodontic practice. The more powerful tool you use, the easier it is when you handle these difficult malocclusions. One of the most challenging malocclusions in the orthodontic practice might be surgical cases asking for nonsurgical treatment. Camouflage treatments without orthognathic surgeries may lead to compromised treatment results. Skeletal anchorage devices can help the anchorage for improved occlusions and facial esthetics under appropriate diagnosis and treatment plan. Another category of challenging malocclusions is impactions and even canine transpositions, which are greatly simplified in mechanics with an improved success rate with the advent of TADs. Mutilated dentitions with multiple teeth missing are also very difficult because of lack of appropriate anchorage. With the help of TADs, we may treat these challenging malocclusions with ease, which otherwise would be deemed as a mission impossible without the help of TADs and interdisciplinary treatment. There are many more challenging malocclusions like retreatment due to the dissatisfaction with the previous treatment or even nightmares of orthodontists, the ankylosis. The applications of TADs in these challenging malocclusions will be discussed.