In the era of new and mostly effective therapeutic protocols, multiple myeloma 
still tends to be a hard-to-treat hematologic cancer. This hallmark of the 
disease is in fact a sequel to drug resistant phenotypes persisting initially or 
emerging in the course of treatment. Furthermore, the heterogeneous nature of 
multiple myeloma makes treating patients with the same drug challenging because 
finding a drugable oncogenic process common to all patients is not yet feasible, 
while our current knowledge of genetic/epigenetic basis of multiple myeloma 
pathogenesis is outstanding. Nonetheless, bone marrow microenvironment 
components are well known as playing critical roles in myeloma tumor cell 
survival and environment-mediated drug resistance happening most possibly in all 
myeloma patients. Generally speaking, however; real mechanisms underlying drug 
resistance in multiple myeloma are not completely understood. The present review 
will discuss the latest findings and concepts in this regard. It reviews the 
association of important chromosomal translocations, oncogenes (e.g. TP53) 
mutations and deranged signaling pathways (e.g. NFκB) with drug response in 
clinical and experimental investigations. It will also highlight how bone marrow 
microenvironment signals (Wnt, Notch) and myeloma cancer stem cells could 
contribute to drug resistance in multiple myeloma.