Many aspects of metal accumulation in aquatic invertebrates (i.e. toxicity, tolerance and trophic transfer) can be understood by examining the subcellular partitioning of accumulated metal. In this paper, we use a compartmentalization approach to interpret the significance of metal, species and size dependence in the subcellular partitioning of Cd and Zn in the bivalvesMacoma balthicaandPotamocorbula amurensis. Of special interest is the compartmentalization of metal as metal-sensitive fractions (MSF) (i.e. organelles and heat-sensitive proteins, termed ‘enzymes’ hereafter) and biologically detoxified metal (BDM) (i.e. metallothioneins MT and metal-rich granules MRG). Clams from San Francisco Bay, CA, were exposed for 14 d to seawater (20‰ salinity) containing 3.5 μg l–1Cd and 20.5 μg l–1Zn, including109Cd and65Zn as radiotracers. Uptake was followed by 21 d of depuration. The subcellular partitioning of metal within clams was examined following exposure and loss.P. amurensisaccumulated ~22× more Cd and ~2× more Zn thanM. balthica. MT played an important role in the storage of Cd inP. amurensis, while organelles were the major site of Zn accumulation. InM. balthica, Cd and Zn partitioned similarly, although the pathway of detoxification was metal-specific (MRG for Cd; MRG and MT for Zn). Upon loss,M. balthicadepurated ~40% of Cd with Zn being retained;P. amurensisretained Cd and depurated Zn (~40%). During efflux, Cd and Zn concentrations in the MSF compartment of both clams declined with metal either being lost from the animal or being transferred to the BDM compartment. Subcellular compartmentalization was also size-dependent, with the importance of BDM increasing with clam size; MSF decreased accordingly. We hypothesized that progressive retention of metal as BDM (i.e. MRG) with age may lead to size dependency of metal concentrations often observed in some populations ofM. balthica.