Rampant inter-patient and intra-tumor heterogeneity present formidable challenges in the clinical management of triple-negative breast cancer (TNBC) and mandate a “divide-and–conquer” approach wherein deep biomarker profiling drives patient segmentation and development of customized treatments. Genomic and proteomic studies have uncovered several TNBC subtypes each of which represents a distinct disease pathobiology and harbors unique actionable targets that may illuminate sensitivities to specific classes of therapeutics. This review details the mind-boggling complexity of TNBC, its ramifications for prognosis and therapeutic response, and discusses what treatments might befit each TNBC subtype. Additionally, focused efforts geared toward translating these findings into the clinic are urged. This review also supports an evidence-based paradigm shift towards inclusion of agents that target the mechanisms that drive intra-tumor heterogeneity, in order to improve long-term outcomes for TNBC patients.