An ever-increasing number of studies highlight the role of mutant p53 proteins in the alteration of cancer cell secretome and in the modification of tumour microenvironment, sustaining an invasive phenotype of cancer cell. The knowledge of the molecular mechanisms underlying the interplay between mutant p53 proteins and the microenvironment is becoming fundamental for the identification of both efficient anticancer therapeutic strategies and novel serum biomarkers. In this review, we summarize the novel findings concerning the regulation of secreted molecules by cancer cells bearing mutant TP53 gene. In particular, we highlight data from available literature suggesting that mutant p53 proteins are able to : i) alter the secretion of enzymes involved in the modulation of extracellular matrix components; ii) alter the secretion of inflammatory cytokines; iii) increase the extracellular acidification; and iv) regulate the crosstalk between cancer and stromal cells.