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Convolutional Neural Networks (CNNs) with U-shaped architectures have dominated medical image segmentation, which is crucial for various clinical purposes. However, the inherent locality of convolution makes CNNs fail to fully exploit global context, essential for better recognition of some structures, e.g., brain lesions. Transformers have recently proven promising performance on vision tasks, including semantic segmentation, mainly due to their capability of modeling long-range dependencies. Nevertheless, the quadratic complexity of attention makes existing Transformer-based models use self-attention layers only after somehow reducing the image resolution, which limits the ability to capture global contexts present at higher resolutions. Therefore, this work introduces a family of models, dubbed Factorizer, which leverages the power of low-rank matrix factorization for constructing an end-to-end segmentation model. Specifically, we propose a linearly scalable approach to context modeling, formulating Nonnegative Matrix Factorization (NMF) as a differentiable layer integrated into a U-shaped architecture. The shifted window technique is also utilized in combination with NMF to effectively aggregate local information. Factorizers compete favorably with CNNs and Transformers in terms of accuracy, scalability, and interpretability, achieving state-of-the-art results on the BraTS dataset for brain tumor segmentation and ISLES'22 dataset for stroke lesion segmentation. Highly meaningful NMF components give an additional interpretability advantage to Factorizers over CNNs and Transformers. Moreover, our ablation studies reveal a distinctive feature of Factorizers that enables a significant speed-up in inference for a trained Factorizer without any extra steps and without sacrificing much accuracy. The code and models are publicly available at https://github.com/pashtari/factorizer.