This invention employs multiple ultrasound pulse firings of either alternating phase and/or amplitude to detect nonlinear fundamental and subharmonic signals from microbubble contrast agents within living tissue, at high frequencies (≧15 MHz), e.g., with a linear array transducer. It can be shown that the contrast-to-tissue ratio (CTR) decreases with increasing ultrasound frequency because of nonlinear ultrasound propagation in tissue. However, using the subharmonic signal in addition to the nonlinear fundamental harmonic component, rather than the conventional second harmonic used at lower frequencies, provides appreciable signal strength to overcome the limitations of nonlinear tissue propagation. Additionally, the method provides for the ability to switch, at some desired frequency above 20 MHz, into a purely alternating phase inversion acquisition, in combination with bandpass filtering of the subharmonic frequency band, minimizing the losses in CTR as the frequency increases. This maintains contrast sensitivity for more limited fields of view, as penetration depth will be limited at higher frequencies. Thus, within the same micro-ultrasound imaging system, many applications of microbubble detection can be achieved with a wide range of frequencies that covers both resolution and sensitivity requirements.