Over the course of a patient’s treatment, they frequently receive multiple drugs. These treatments can either be as combination therapy or sequential treatment after the first has failed. Regardless, rare cancer cells still survive and develop resistance. Our development of complex treatment strategies has outpaced our studies of how such resistance develops in the first place as we continue to study how treatment resistance originates one drug at a time. Instead, we take the stance that studying how rare cells develop resistance to many different treatments could identify cell states to be targeted for broadly reducing treatment resistance. To this end, we performed highly scaled clonal tracing with scRNA-seq to study how clonal populations of melanoma cells survive microenvironmental stress (mimicking hypoxia with CoCl2 or acidic media), small-molecule therapies (MEKi or BRAFi), and broad-spectrum chemotherapeutics (doxorubicin and cisplatin). By tracing clones through initial treatment with each of these agents, we identified stem-like cells, characterized by high expression of CD44, that map to resistance to multiple different treatments. Within a single treatment, we found that different initial gene expression states can cause cells to take divergent paths towards resistance. We also asked how clonal populations of melanoma cells change over multiple rounds of treatment and how these changes affect response to secondary treatments. Here we identified a form of acquired multi-treatment resistance where developing resistance to combination BRAFi/MEKi caused previously CoCl2-sensitive clones to express IL6ST and become CoCl2-resistant. Within the same clonal tracing experiment, we also showed that clonal differences played a role in long-term resistance to a single treatment where EGFR-high clones were more resistant to combination BRAFi/MEKi than NGFR-high clones during prolonged treatment. Overall, these findings highlight the power of mapping how treatment resistance originates across multiple different treatments on a clone-by-clone basis. Additionally, these findings and methods provide a framework that can be used to identify the proper ordering of treatment to eliminate resistant cell states over the course of treatment.