Intercellular communications play a major role in tissue homeostasis. In pathologies such as cancer, cellular interactions within the tumor microenvironment (TME) contribute to tumor progression and resistance to therapy. Tunneling nanotubes (TNTs) are newly discovered long-range intercellular connections that allow the exchange between cells of various cargos, ranging from ions to whole organelles such as mitochondria. TNT-transferred mitochondria were shown to change the metabolism and functional properties of recipient cells as reported for both normal and cancer cells. Metabolic plasticity is now considered a hallmark of cancer as it notably plays a pivotal role in drug resistance. The acquisition of cancer drug resistance was also associated to TNT-mediated mitochondria transfer, a finding that relates to the role of mitochondria as a hub for many metabolic pathways. In this review, we first give a brief overview of the various mechanisms of drug resistance and of the cellular communication means at play in the TME, with a special focus on the recently discovered TNTs. We further describe recent studies highlighting the role of the TNT-transferred mitochondria in acquired cancer cell drug resistance. We also present how changes in metabolic pathways, including glycolysis, pentose phosphate and lipid metabolism, are linked to cancer cell resistance to therapy. Finally, we provide examples of novel therapeutic strategies targeting mitochondria and cell metabolism as a way to circumvent cancer cell drug resistance. Mechanisms of drug resistance Resistance to cancer therapy is still a major obstacle for effective and lasting treatment, resulting in relapse, metastasis and reduced overall survival. Many mechanisms have been described that foster this resistance, including both cell autonomous (or intrinsic) and extrinsic processes, the latter greatly resulting from the tumor microenvironment (TME) complexity [1,2]. It is indeed becoming increasingly evident that tumors do not behave as masses of homogeneous malignant cells, but rather as complex, full-fledged 'organs' in dynamic progression through time and space, resulting in enhanced tumor fitness and resistance to therapy [3,4]. Drug resistance intrinsic processes Understanding the drug resistance molecular mechanisms is more crucial than ever in order to achieve effective and long-lasting cancer therapy. The mechanisms of drug resistance include drug transporters, DNA damage repair (DDR) and genomic instability, apoptosis inhibition and metabolic adaptation [5,6]. Unfortunately, these mechanisms often overlap in the context of cancer, adding an extra layer of complexity that often precludes the full deciphering of all resistance causes.