Polyhydroxyalkanoates (PHAs) that contain varied monomers with different chain lengths/structures were normally synthesized when a structurally-related precursor was present. The biosynthesis of PHAs from unrelated carbon sources in microorganisms including Escherichia coli met many challenges in the past. Recently, with the development of metabolic engineering and synthetic biology, the production of PHAs from unrelated carbon sources obtained a breakthrough. Polyesters containing 2-hydroxypropionate, 3-hydroxypropionate, 4-hydroxybutyrate, 3-hydroxyvalarate, and medium-chain-length 3-hydroxyalkanoate monomers can all be synthesized in E. coli by integrating exogenous or endogenous pathways and/or genes. This review will summarize the progresses in this area. In addition, the strategies that lead to the production of PHAs with varied monomers and high polymer content in the cell are discussed.