The transition from a normal to a cancerous cell involves a multistep process driven by genetic alterations. Malignant cells progressively acquire traits that enhance their survival within the host, including the ability to evade apoptosis, stimulate neovascularization, and escape immune surveillance. These adaptations allow cancer to grow uncontrollably, invade adjacent tissues, and metastasize to distant organs, ultimately impairing normal physiological functions and complicating treatment efforts. Among the most significant clinical challenges is chemotherapy resistance, which diminishes the effectiveness of conventional therapies and contributes to disease progression. Addressing this issue requires integrated and multidisciplinary approaches. This review investigates and compares the mechanisms of chemotherapy resistance identified in humans and companion animals. By examining both shared and species-specific features, this analysis aims to support the development of more effective and translational treatment strategies.