Cell migration and invasion require regulated turnover of integrin-dependent adhesion complexes. RIAM is an adaptor protein mediating talin recruitment to the cell membrane, whose depletion leads to defective melanoma cell migration and invasion. Here we investigated the potential involvement of RIAM in focal adhesion (FA) dynamics. RIAM-depleted melanoma and breast carcinoma cells displayed an increased number, size and stability of FAs, which accumulated centrally located at the ventral cell surface, a phenotype caused by defective FA disassembly. Impairment in FA disassembly due to RIAM knocking down correlated with deficient integrin-dependent MEK-Erk1/2 activation, and importantly, overexpression of constitutively active MEK resulted in rescue of FA disassembly and recovery of cell invasion. Furthermore, RIAM-promoted RhoA activation following integrin engagement was needed for subsequent Erk1/2 activation, and RhoA overexpression partially rescued the FA phenotype in RIAM-depleted cells, suggesting a functional role also for RhoA downstream of RIAM, but upstream of Erk1/2. In addition, RIAM knock down led to enhanced phosphorylation of paxillin Tyr118 and Tyr31. However, expression of phosphomimetic and non-phosphorylatable mutants at these paxillin residues indicated that paxillin hyper-phosphorylation is a subsequent consequence of the blockade of FA disassembly, but does not cause the FA phenotype. RIAM depletion also weakened association between FA proteins, suggesting that it may play important adaptor roles for the correct assembly of adhesion complexes. Our data indicate that integrin-triggered, RIAM-dependent MEK activation may represent a key feed-back event required for efficient FA disassembly, which may contribute to explain the role of RIAM in cell migration and invasion.