Traditional anticancer chemotherapeutics targeting DNA replication and cell division have severe side effects, but they have proved to be highly successful in treating some cancers. Drugs targeting signalling oncoproteins that have gained tumour-driving functions through mutations or overexpression were subsequently developed to increase specificity and thus reduce side effects, but have limitations such as the development of resistance. Now, a new wave of small-molecule anticancer agents is emerging, targeting complex multicomponent cellular machineries—including chromatin modifiers, heat shock protein chaperones and the proteasome—which thus interfere with those support systems that are more essential for cancer cells than for normal cells. Here, we provide our perspective on the advantages and limitations of agents that target tumour-supportive cellular machineries (other than those involving DNA replication), comparing them with agents that target signalling intermediates.