The rapid development of green energy sources and new medical technologies contributes to the increased exploitation of rare earth elements (REEs). They can be subdivided into light (LREEs) and heavy (HREEs) REEs. Mining, industrial processing, and end-use practices of REEs has led to elevated environmental concentrations and raises concerns about their toxicity to organisms and their impact on ecosystems. REE toxicity has been reported, but its precise underlying molecular effects have not been well described. Here, transcriptomic and proteomic approaches were combined to decipher the molecular responses of the model organism Saccharomyces cerevisiae to La (LREE) and Yb (HREE). Differences were observed between the early and late responses to La and Yb. Several crucial pathways were modulated in response to both REEs, such as oxidative-reduction processes, DNA replication, and carbohydrate metabolism. REE-specific responses involving the cell wall and pheromone signalling pathways were identified, and these responses have not been reported for other metals. REE exposure also modified the expression and abundance of several ion transport systems, with strong discrepancies between La and Yb. These findings are valuable for prioritizing key genes and proteins involved in La and Yb detoxification mechanisms that deserve further characterization to better understand REE environmental and human health toxicity.