Introduction Although total knee arthroplasty (TKA) is a very frequent surgery, one in five patients is not completely satisfied. Mechanical alignment (MA) is the most popular technique for implanting TKA. However, to improve clinical outcomes, new techniques that aim to rebuild the native alignment of the knee have been developed. Objective The aim of this study is to perform a systematic review of the available clinical trials and observational studies comparing clinical and radiological outcomes of different methods of alignment (kinematic, anatomic, functional) to MA. Methods A systematic review is performed comparing results of patient reported outcome measures (PROMs) questionnaires (WOMAC, OKS, KSS, KOOS, FJS), radiological angles (HKA, mLDFA, MPTA, JLOA, femoral rotation and tibial slope) and range of motion (ROM). Results Kinematic and functional alignment show a slight tendency to obtain better PROMs compared to mechanical alignment. Complication rates were not significantly different between groups. Nevertheless, these results are not consistent in every study. Anatomic alignment showed no significant differences compared to mechanical alignment. Conclusion Kinematic alignment is an equal or slightly better alternative than mechanical alignment for patients included in this study. However, the difference between methods does not seem to be enough to explain the high percentage of dissatisfied patients. Studies implementing lax inclusion and exclusion criteria would be needed to resemble conditions of patients assisted in daily surgical practice. It would be interesting to study patient’s knee phenotypes, to notice if any method of alignment is significantly better for any constitutional deviation.