Malaria remains a major public health problem with hundreds of thousands of deaths annually. It is caused by parasites of the Plasmodium genus, which exhibit striking adaptability: The single-celled eukaryotes undergo several complex developmental transitions in order to inhabit vastly different environments in both the human and mosquito hosts, and also have readily been developing resistance against antimalarial drugs used in the field. In this thesis, recently developed technologies for single-cell transcriptomics (scRNAseq) were exploited to uncover mechanisms of both differentiation and drug resistance that involve heterogeneous populations of malaria parasites. First, we characterized the transcriptional signature of a key developmental transition that is necessary for transmission from humans to mosquitos. Parasites replicate asexually within human red blood cells and during each cycle, a morphologically indistinguishable subpopulation of parasites commits to initiating non-replicative sexual differentiation in the next host cell by expressing the cell fate-determining transcription factor AP2-G in the current host cell. However, which genes are turned on immediately downstream of AP2-G has remained elusive. Using scRNAseq, we found that sexually committed, AP2-G-positive replicative stages express additional regulators of gene expression, such as transcription factors and epigenetic regulators, which may act to facilitate the expression and/or repression of genes that are necessary for the initiation of sexual development in the subsequent cell cycle. Second, we identified a putative translational regulator contributing to resistance against the front-line antimalarial artemisinin. Resistance-conferring point mutations in the parasite protein Kelch13 have been shown to lead to low-level activation of the parasite’s integrated stress response (ISR) which has a protective effect against artemisinin through an unclear mechanism. Furthermore, only a subpopulation of resistant parasites ever survives drug exposure, implying an underlying heterogeneity. Using scRNAseq, we found expansion of a subpopulation in Kelch13 mutant parasites that is chiefly characterized by transcription of the putative positive translational regulator D123, while we conversely observed reduced D123 protein levels. Analogous inverse changes in D123 expression are produced by experimental activation of the ISR, and genetically manipulating D123 expression modulates sensitivity to artemisinin, establishing it as a stress-responsive gene that contributes to artemisinin resistance in Kelch13-mutant malaria parasites.