Cancer mechanics have lately emerged as a distinct tumor feature that promotes tumor development, invasion, and metastasis. Tumor mechanosensing involves a mechanical interplay between cancer cells, extracellular matrix, and cells of the surrounding stroma. Mechanoreceptors sense alterations of the extracellular mechanical cues and activate signaling molecules, which mediate oncogenic transcription in favor of cancer initiation, survival, growth, and metastasis. Furthermore, alterations of the matrix rigidity and activation of mechano-induced transcriptional regulators has been strongly associated with resistance to anti-cancer agents. In this context, new mechanosensitive molecules arise as potential therapeutic targets. Therefore, tumor mechanosignaling represents a promising field that can potentially offer new combination regimens to overcome drug resistance, but also suggest novel targeting strategies.