Brain tumor segmentation from MRIs has always been a challenging task for radiologists, therefore, an automatic and generalized system to address this task is needed. Among all other deep learning techniques used in medical imaging, U-Net-based variants are the most used models found in the literature to segment medical images with respect to different modalities. Therefore, the goal of this paper is to examine the numerous advancements and innovations in the U-Net architecture, as well as recent trends, with the aim of highlighting the ongoing potential of U-Net being used to better the performance of brain tumor segmentation. Furthermore, we provide a quantitative comparison of different U-Net architectures to highlight the performance and the evolution of this network from an optimization perspective. In addition to that, we have experimented with four U-Net architectures (3D U-Net, Attention U-Net, R2 Attention U-Net, and modified 3D U-Net) on the BraTS 2020 dataset for brain tumor segmentation to provide a better overview of this architecture’s performance in terms of Dice score and Hausdorff distance 95%. Finally, we analyze the limitations and challenges of medical image analysis to provide a critical discussion about the importance of developing new architectures in terms of optimization.